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KAWABATA Atsufumi

    Department of Pharmacy　Professor
Last Updated :2024/04/25

Researcher Information

Degree

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URL

J-Global ID

Research Interests

  • ラジカル   プロテアーゼ   受容体   Radical   Protease   Receptor   

Research Areas

  • Life sciences / Pharmacology
  • Life sciences / Pharmaceuticals - health and biochemistry

Education

  •        - 1985  Kindai University  薬学系研究科  薬学
  •        - 1985  Kinki University  Graduate School, Division of Pharmaceutical Sciences
  •        - 1983  Kindai University  Faculty of Pharmacy  薬学
  •        - 1983  Kinki University  Faculty of Pharmaceutical Science

Association Memberships

  • 日本疼痛学会   日本薬学会   日本薬理学会   

Published Papers

  • Shiori Iwane; Wataru Nemoto; Tomoyoshi Miyamoto; Tomonori Hayashi; Masayuki Tanaka; Kazuki Uchitani; Tatsuya Muranaka; Masanori Fujitani; Yuichi Koizumi; Atsushi Hirata; Maho Tsubota; Fumiko Sekiguchi; Koichi Tan-No; Atsufumi Kawabata
    Scientific Reports Springer Science and Business Media LLC 14 (1) 2024/01 
    Abstract Given possible involvement of the central and peripheral angiotensin system in pain processing, we conducted clinical and preclinical studies to test whether pharmacological inhibition of the angiotensin system would prevent diabetic peripheral neuropathy (DPN) accompanying type 2 diabetes mellitus (T2DM). In the preclinical study, the nociceptive sensitivity was determined in leptin-deficient ob/ob mice, a T2DM model. A clinical retrospective cohort study was conducted, using the medical records of T2DM patients receiving antihypertensives at three hospitals for nearly a decade. In the ob/ob mice, daily treatment with perindopril, an angiotensin-converting enzyme inhibitor (ACEI), or telmisartan, an angiotensin receptor blocker (ARB), but not amlodipine, an L-type calcium channel blocker (CaB), significantly inhibited DPN development without affecting the hyperglycemia. In the clinical study, the enrolled 7464 patients were divided into three groups receiving ACEIs, ARBs and the others (non-ACEI, non-ARB antihypertensives). Bonferroni’s test indicated significantly later DPN development in the ARB and ACEI groups than the others group. The multivariate Cox proportional analysis detected significant negative association of the prescription of ACEIs or ARBs and β-blockers, but not CaBs or diuretics, with DPN development. Thus, our study suggests that pharmacological inhibition of the angiotensin system is beneficial to prevent DPN accompanying T2DM.
  • Yoshihito Kasanami; Takashi Yamamoto; Tomoyoshi Miyamoto; Sumio Matzno; Mikio Sakakibara; Masahiro Iwaki; Atsufumi Kawabata
    Biological and Pharmaceutical Bulletin Pharmaceutical Society of Japan 46 (12) 1699 - 1705 0918-6158 2023/12
  • Shiori Tomita; Fumiko Sekiguchi; Katsuki Naoe; Shiyu Shikimi; Yoshihito Kasanami; Maya Ohigashi; Maho Tsubota; Atsufumi Kawabata
    Journal of pharmacological sciences 152 (2) 86 - 89 2023/06 
    Cav3.2, a T-type calcium channel (T-channel) family member, is expressed in the nociceptors and spinal cord, and its activity is largely suppressed by zinc under physiological conditions. In rats, intrathecal and intraplantar administration of a zinc chelator, TPEN, caused T-channel-dependent mechanical hyperalgesia, and the intraplantar, but not intrathecal, TPEN induced Cav3.2 upregulation in the dorsal root ganglion. In mice, intraplantar TPEN also caused mechanical allodynia, which was abolished by T-channel inhibitors or Cav3.2 gene deletion. Together, spinal and peripheral zinc deficiency appears to enhance Cav3.2 activity in the spinal postsynaptic neurons and nociceptors, respectively, thereby promoting pain.
  • Fumiko Sekiguchi; Nene Koike; Yasuhiro Shimada; Kaho Sugimoto; Hiroshi Masuda; Takashi Nakamura; Hiroaki Yamaguchi; Genzoh Tanabe; Shinsuke Marumoto; Yoshihito Kasanami; Maho Tsubota; Tsuyako Ohkubo; Shigeru Yoshida; Atsufumi Kawabata
    Redox biology 59 102579 - 102579 2023/02 
    Poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132), an organogermanium, is hydrolyzed to 3-(trihydroxygermyl)propanoic acid (THGP) in aqueous solutions, and reduces inflammation, pain and cancer, whereas the underlying mechanisms remain unknown. Sulfides including H2S, a gasotransmitter, generated from l-cysteine by some enzymes including cystathionine-γ-lyase (CSE), are pro-nociceptive, since they enhance Cav3.2 T-type Ca2+ channel activity expressed in the primary afferents, most probably by canceling the channel inhibition by Zn2+ linked via coordinate bonding to His191 of Cav3.2. Given that germanium is reactive to sulfur, we tested whether THGP would directly trap sulfide, and inhibit sulfide-induced enhancement of Cav3.2 activity and sulfide-dependent pain in mice. Using mass spectrometry and 1H NMR techniques, we demonstrated that THGP directly reacted with sulfides including Na2S and NaSH, and formed a sulfur-containing reaction product, which decreased in the presence of ZnCl2. In Cav3.2-transfected HEK293 cells, THGP inhibited the sulfide-induced enhancement of T-type Ca2+ channel-dependent membrane currents. In mice, THGP, administered systemically or locally, inhibited the mechanical allodynia caused by intraplantar Na2S. In the mice with cyclophosphamide-induced cystitis and cerulein-induced pancreatitis, which exhibited upregulation of CSE in the bladder and pancreas, respectively, systemic administration of THGP as well as a selective T-type Ca2+ channel inhibitor suppressed the cystitis-related and pancreatitis-related visceral pain. These data suggest that THGP traps sulfide and inhibits sulfide-induced enhancement of Cav3.2 activity, leading to suppression of Cav3.2-dependent pain caused by sulfide applied exogenously and generated endogenously.
  • Takashi Maeda; Fumiko Sekiguchi; Kenji Mitani; Ryosuke Yamagata; Maho Tsubota; Shigeru Yoshida; Atsufumi Kawabata
    Biochemical and biophysical research communications 639 142 - 149 2023/01 
    Irregular regeneration or inappropriate remodeling of the axons of the primary afferent neurons after peripheral nerve trauma could be associated with the development of neuropathic pain. We analyzed the molecular mechanisms for the neuritogenesis and neurite outgrowth caused by prostaglandin E2 (PGE2) in mouse dorsal root ganglion (DRG) neurons, and evaluated their opioid modulation. PGE2 in combination with IBMX, a phosphodiesterase inhibitor, caused neuritogenesis/neurite outgrowth in DRG cells, an effect abolished by a prostanoid EP4, but not EP2, receptor antagonist, and inhibitors of adenylyl cyclase or protein kinase A (PKA). Blockers of T-type Ca2+ channels (T-channels), that are responsible for window currents involving the sustained low-level Ca2+ entry at voltages near the resting membrane potentials and can be functionally upregulated by PKA, inhibited the neuritogenesis/neurite outgrowth caused by PGE2/IBMX or dibutylyl cyclic AMP, a PKA activator, in DRG neurons, an inhibitory effect mimicked by ZnCl2 and ascorbic acid that block Cav3.2, but not Cav3.1 or Cav3.3, T-channels. Morphine and DAMGO, μ-opioid receptor (MOR) agonists, suppressed the neuritogenesis and/or neurite outgrowth induced by PGE2/IBMX in DRG neurons and also DRG neuron-like ND7/23 cells, an effect reversed by naloxone or β-funaltrexamine, a selective MOR antagonist. Our data suggest that the EP4 receptor/PKA/Cav3.2 pathway is involved in the PGE2-induced neuritogenesis/neurite outgrowth in DRG neurons, which can be suppressed by MOR stimulation. We propose that MOR agonists including morphine in the early phase after peripheral nerve trauma might delay the axonal regeneration of the primary afferent neurons but prevent the development of neuropathic pain.
  • Shiori Tomita; Fumiko Sekiguchi; Maho Tsubota; Atsufumi Kawabata
    Biological & pharmaceutical bulletin 46 (9) 1343 - 1346 2023 
    Cav3.2 channels belong to the T-type calcium channel (T-channel) family, i.e., low voltage-activated calcium channels, and are abundantly expressed in the nociceptors, playing a principal role in the development of pathological pain. The channel activity of Cav3.2 is suppressed by zinc under physiological conditions. We thus tested whether dietary zinc deficiency would cause Cav3.2-dependent nociceptive hypersensitivity in mice. In the mice fed with zinc deficient diet for 2 weeks, plasma zinc levels declined by more than half, and mechanical allodynia developed. The dietary zinc deficiency-induced allodynia was restored by T-channel inhibitors or by Cav3.2 gene silencing. These data demonstrate that zinc deficiency induces Cav3.2-dependent nociceptive hypersensitivity in mice, thereby suggesting that pain experienced by patients with diseases accompanied by zinc deficiency (e.g., chronic kidney disease) might involve the increased Cav3.2 activity.
  • Yoshihito Kasanami; Chihiro Ishikawa; Takahiro Kino; Momoka Chonan; Naoki Toyooka; Yasuhiro Takashima; Yuriko Iba; Fumiko Sekiguchi; Maho Tsubota; Tsuyako Ohkubo; Shigeru Yoshida; Atsushi Kawase; Takuya Okada; Atsufumi Kawabata
    European journal of medicinal chemistry 243 114716 - 114716 2022/08 
    T-type Ca2+ channels (T-channels), particularly Cav3.2 and Cav3.1 isoforms, are promising targets for treating various diseases including intractable pain. Given the potent inhibitory activity of pimozide, an antipsychotic, against T-channels, we conducted structure-activity relationship studies of pimozide derivatives, and identified several compounds including 3a, 3s, and 4 that had potency comparable to that of pimozide in inhibiting T-channels, but little binding affinity to dopamine D2 receptors. The introduction of a phenylbutyl group on the benzoimidazole nuclei of pimozide was considered a key structural modification to reduce the binding affinity to D2 receptors. Those pimozide derivatives potently suppressed T-channel-dependent somatic and visceral pain in mice, without causing any motor dysfunctions attributable to D2 receptor blockade, including catalepsy. The present study thus provides an avenue to develop novel selective T-channel inhibitors available for pain management via the structural modification of existing medicines.
  • Tomoyoshi Miyamoto; Risa Domoto; Fumiko Sekiguchi; Riki Kamaguchi; Rika Nishimura; Misato Matsuno; Maho Tsubota; Masanori Fujitani; Shigekatsu Hatanaka; Yuichi Koizumi; Dengli Wang; Masahiro Nishibori; Atsufumi Kawabata
    Journal of Pharmacological Sciences Elsevier BV 148 (3) 315 - 325 1347-8613 2022/03 
    Oxaliplatin often induces peripheral neuropathy, a dose-limiting adverse reaction, and in rare cases leads to sinusoidal obstruction syndrome. We thus conducted a retrospective cohort study to examine the relationship between oxaliplatin-induced peripheral neuropathy (OIPN) and hepatic impairment, and then perform a fundamental study to analyze the underlying mechanisms. Analysis of medical records in cancer patients treated with oxaliplatin indicated that laboratory test parameters of hepatic impairment including AST, ALT and APRI (AST to platelet ratio index) moderately increased during oxaliplatin treatment, which was positively correlated with the severity of OIPN (grades 1-4), and associated with later incidence of survivors with OIPN grades ≥2. In mice, hepatic injury induced by CCl4 or ethanol accelerated OIPN in mice, an effect prevented by inactivation of high mobility group box 1 (HMGB1), known to participate in OIPN, by the neutralizing antibody or thrombomodulin alfa capable of promoting its thrombin-dependent degradation. Oxaliplatin also aggravated the hepatic injury in mice. CCl4 released HMGB1 from cultured hepatic parenchymal cells, and oxaliplatin at clinically achievable concentrations released HMGB1 from hepatic parenchymal and non-parenchymal cells. Our clinical and preclinical data suggest that the development of mild hepatic impairment during oxaliplatin treatment is associated with later aggravation of OIPN.
  • Risa Domoto; Fumiko Sekiguchi; Riki Kamaguchi; Maiko Iemura; Hiroki Yamanishi; Maho Tsubota; Dengli Wang; Masahiro Nishibori; Atsufumi Kawabata
    Journal of pharmacological sciences 148 (1) 156 - 161 2022/01 
    We examined the role of ATP and high mobility group box 1 (HMGB1) in paclitaxel-induced peripheral neuropathy (PIPN). PIPN in mice was prevented by HMGB1 neutralization, macrophage depletion, and P2X7 or P2X4 blockade. Paclitaxel and ATP synergistically released HMGB1 from macrophage-like RAW264.7 cells, but not neuron-like NG108-15 cells. The paclitaxel-induced HMGB1 release from RAW264.7 cells was accelerated by co-culture with NG108-15 cells in a manner dependent on P2X7 or P2X4. Paclitaxel released ATP from NG108-15 cells, but not RAW264.7 cells. Thus, PIPN is considered to involve acceleration of HMGB1 release from macrophages through P2X7 and P2X4 activation by neuron-derived ATP.
  • Ieda Shoko; Miyamoto Tomoyoshi; Hosomi Kouichi; Takegami Manabu; Kawabata Atsufumi
    The Journal of Community Pharmacy and Pharmaceutical Sciences Pharmacy Society of Japan advpub 1884-3077 2022 
    Objective: Pharmacy students learn the “brand names” of many drugs throughout clinical training, and their drug recognition skill in “generic names” might decline thereafter. To evaluate this, we conducted tests to assess students’ recognition of drugs in both “brand” and “generic” names before and after clinical training. Method: The participants were 64 students undergoing clinical pharmacy training at Kindai University Hospital. Mark-sheet tests concerning pharmacology of drugs in both “brand” and “generic” names were conducted 3 times, before and after community pharmacy training and after hospital pharmacy training. Results: After clinical pharmacy training, students’ drug recognition skill in “brand name” significantly elevated, but that in “generic name” remained constant. Conclusions: Unexpectedly, many students maintained their drug recognition skill in “generic name” after clinical pharmacy training. Nonetheless, educational programs to make students conscious of “generic name” linking with “brand name” during clinical training might be beneficial to promote overall skills in clinical pharmacy.
  • Shiori Hiramoto; Hajime Asano; Tomoyoshi Miyamoto; Manabu Takegami; Atsufumi Kawabata
    PLOS ONE Public Library of Science (PLoS) 16 (12) e0261473 - e0261473 2021/12 
    Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse reaction in cancer patients treated with several cytotoxic anticancer agents including paclitaxel. Duloxetine, an antidepressant known as a serotonin-noradrenalin reuptake inhibitor, is the only agent that has moderate evidence for the use to treat painful CIPN. The present retrospective cohort study aimed to analyze risk factors for paclitaxel-induced peripheral neuropathy (PIPN), and investigate ongoing prescription drug use for PIPN in Japan. Female breast and gynecologic cancer patients who underwent paclitaxel-based chemotherapy at a single center in Japan between January 2016 and December 2019 were enrolled in this study. Patients’ information obtained from electronic medical records were statistically analyzed to test possible risk factors on PIPN diagnosis. Patients’ age, total paclitaxel dose, the history of female hormone-related diseases, hypertension and body mass index (BMI), but not additional platinum agents, were significantly associated with increased PIPN diagnosis. Drugs prescribed for PIPN included duloxetine, pregabalin, mecobalamin and Goshajinkigan, a polyherbal medicine, regardless of poor evidence for their effectiveness against CIPN, and were greatly different between breast and gynecologic cancer patients diagnosed with PIPN at the departments of Surgery and Gynecology, respectively. Thus, older age, greater total paclitaxel dose, the history of estrogen-related diseases, hypertension and BMI are considered risk factors for PIPN in paclitaxel-based chemotherapy of female cancer patients. It appears an urgent need to establish a guideline of evidence-based pharmacotherapy for PIPN.
  • Tomonori Hayashi; Tomoyoshi Miyamoto; Noriaki Nagai; Atsufumi Kawabata
    Scientific Reports Springer Science and Business Media LLC 11 (1) 17157 - 17157 2021/12 
    AbstractTo identify risk factors for the prognosis of prostate cancer (PC), we retrospectively analyzed the impact of lifestyle-related disorders as well as PC characteristics at initial diagnosis on the progression to castration-resistant PC (CRPC) in PC patients undergoing hormone therapy. Of 648 PC patients, 230 who underwent hormone therapy and met inclusion criteria were enrolled in this study. CRPC developed in 48 patients (20.9%). Univariate analysis using Cox proportional hazard model indicated that newly developed diabetes mellitus (DM) following hormone therapy (postDM), but not preexisting DM, as well as PC characteristics at initial diagnosis including prostate-specific antigen (PSA) ≥ 18 were significantly associated with the progression to CRPC. A similar tendency was also observed in the relationship between newly developed hypertension following hormone therapy and CRPC progression. On the other hand, neither dyslipidemia nor hyperuricemia, regardless the onset timing, exhibited any association with CRPC progression. In multivariate analysis, postDM and PSA ≥ 18 were extracted as independent risk factors for CRPC progression (adjusted hazard ratios, 3.38 and 2.34; p values, 0.016 and 0.019, respectively). Kaplan–Meier analysis and log-rank test clearly indicated earlier progression to CRPC in PC patients who developed postDM or had relatively advanced initial PC characteristics including PSA ≥ 18. Together, the development of lifestyle-related disorders, particularly DM, following hormone therapy, as well as advanced PC characteristics at initial diagnosis is considered to predict earlier progression to CRPC and poor prognosis in PC patients undergoing hormone therapy.
  • Shoko Ieda; Tomoyoshi Miyamoto; Kouichi Hosomi; Manabu Takegami; Atsufumi Kawabata
    Journal of palliative medicine Mary Ann Liebert Inc 25 (4) 570 - 576 1096-6218 2021/10 
    Background: Accurate prognosis in terminal cancer patients is useful to improve their quality of life and also to decide the cessation of fluid administration. Nonetheless, few prognostic indicators are available for prediction of such a short-term life expectancy. Objectives: The present study aimed at evaluating the efficacy of C-reactive protein (CRP)/albumin (CRP/Alb) ratio, prognostic nutritional index (PNI), fibrosis-4 (FIB-4) index, and albumin-bilirubin (ALBI) score in identifying terminal cancer patients who have a life expectancy less than two weeks. Design: Retrospective study. Setting/Subjects: Of 483 patients who died between April 2019 and March 2020 at a single center in Japan, 102 who met the inclusion criteria were enrolled in this study. Measurements: CRP/Alb, PNI, FIB-4, and ALBI were calculated from the laboratory data collected 1-13, 14-27, 28-83, and 168-365 days before death and subjected to statistical analyses. Results: CRP/Alb, PNI, FIB-4, and ALBI values were significantly associated with the time before death during terminal 365 days. CRP/Alb ≥4.4, PNI <30, FIB-4 ≥ 9.4, and ALBI ≥ -1.26 were significantly associated with the transition from the first half to the second half of terminal four weeks. Of those prognostic indicators, three and four combinations provided significantly reliable estimation of a life expectancy less than two weeks. Conclusions: CRP/Alb, PNI, FIB-4, ALBI, and their combinations are considered to help identify cancer patients who have a life expectancy less than two weeks, which is useful to make appropriate end-stage treatment decisions, for example, cessation of artificial hydration therapy.
  • 薬剤による副作用がある高齢慢性心不全患者において、在宅訪問薬剤師の外来受診同行をきっかけに症状改善が見られた1例
    山本 卓資; 松野 純男; 笠波 嘉人; 榊原 幹夫; 岡田 啓; 川畑 篤史
    薬局薬学 (一社)日本薬局学会 13 (2) 148 - 153 1884-3077 2021/10 [Refereed]
  • Maho Tsubota; Takaya Miyazaki; Yuya Ikeda; Yusuke Hayashi; Yui Aokiba; Shiori Tomita; Fumiko Sekiguchi; Dengli Wang; Masahiro Nishibori; Atsufumi Kawabata
    Cells 10 (10) 2021/09 
    Given the role of macrophage-derived high mobility group box 1 (HMGB1) in chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel, we analyzed the role of HMGB1 and macrophages in the CIPN caused by bortezomib, a proteasome-inhibiting chemotherapeutic agent used for the treatment of multiple myeloma. Repeated administration of bortezomib caused CIPN accompanied by early-stage macrophage accumulation in the dorsal root ganglion. This CIPN was prevented by an anti-HMGB1-neutralizing antibody, thrombomodulin alfa capable of accelerating thrombin-dependent degradation of HMGB1, antagonists of the receptor for advanced glycation end-products (RAGE) and C-X-C motif chemokine receptor 4 (CXCR4), known as HMGB1-targeted membrane receptors, or macrophage depletion with liposomal clodronate, as reported in a CIPN model caused by paclitaxel. In macrophage-like RAW264.7 cells, bortezomib as well as MG132, a well-known proteasome inhibitor, caused HMGB1 release, an effect inhibited by caspase inhibitors but not inhibitors of NF-κB and p38 MAP kinase, known to mediate paclitaxel-induced HMGB1 release from macrophages. Bortezomib increased cleaved products of caspase-8 and caused nuclear fragmentation or condensation in macrophages. Repeated treatment with the caspase inhibitor prevented CIPN caused by bortezomib in mice. Our findings suggest that bortezomib causes caspase-dependent release of HMGB1 from macrophages, leading to the development of CIPN via activation of RAGE and CXCR4.
  • Risa Domoto; Fumiko Sekiguchi; Maho Tsubota; Atsufumi Kawabata
    Cells 10 (8) 2021/07 
    A neuroimmune crosstalk is involved in somatic and visceral pathological pain including inflammatory and neuropathic components. Apart from microglia essential for spinal and supraspinal pain processing, the interaction of bone marrow-derived infiltrating macrophages and/or tissue-resident macrophages with the primary afferent neurons regulates pain signals in the peripheral tissue. Recent studies have uncovered previously unknown characteristics of tissue-resident macrophages, such as their origins and association with regulation of pain signals. Peripheral nerve macrophages and intestinal resident macrophages, in addition to adult monocyte-derived infiltrating macrophages, secrete a variety of mediators, such as tumor necrosis factor-α, interleukin (IL)-1β, IL-6, high mobility group box 1 and bone morphogenic protein 2 (BMP2), that regulate the excitability of the primary afferents. Neuron-derived mediators including neuropeptides, ATP and macrophage-colony stimulating factor regulate the activity or polarization of diverse macrophages. Thus, macrophages have multitasks in homeostatic conditions and participate in somatic and visceral pathological pain by interacting with neurons.
  • Tomoyoshi Miyamoto; Shiori Hiramoto; Ayano Kanto; Maho Tsubota; Masanori Fujitani; Hiroki Fukuyama; Shigekatsu Hatanaka; Fumiko Sekiguchi; Yuichi Koizumi; Atsufumi Kawabata
    Journal of pharmacological sciences 146 (1) 49 - 57 2021/05 
    We performed clinical retrospective study in female cancer patients and fundamental experiments in mice, in order to clarify risk factors for paclitaxel-induced peripheral neuropathy (PIPN). In the clinical study, 131 of 189 female outpatients with cancer undergoing paclitaxel-based chemotherapy met inclusion criteria. Breast cancer survivors (n = 40) showed significantly higher overall PIPN (grades 1-4) incidence than non-breast cancer survivors (n = 91). Multivariate sub-analyses of breast cancer survivors showed that 57 years of age or older and endocrine therapy before paclitaxel treatment were significantly associated with severe PIPN (grades 2-4). The age limit was also significantly correlated with overall development of severe PIPN. In the preclinical study, female mice subjected to ovariectomy received repeated administration of paclitaxel, and mechanical nociceptive threshold was assessed by von Frey test. Ovariectomy aggravated PIPN in the mice, an effect prevented by repeated treatment with 17β-estradiol. Repeated administration of thrombomodulin alfa (TMα), known to prevent chemotherapy-induced peripheral neuropathy in rats and mice, also prevented the development of PIPN in the ovariectomized mice. Collectively, breast cancer survivors, particularly with postmenopausal estrogen decline and/or undergoing endocrine therapy, are considered a PIPN-prone subpopulation, and may require non-hormonal pharmacological intervention for PIPN in which TMα may serve as a major candidate.
  • 薬学部生における一般名と商品名による医薬品認識に及ぼす病院実務実習の影響
    家田 正子; 宮本 朋佳; 細見 光一; 高田 充隆; 竹上 学; 川畑 篤史
    日本薬学会年会要旨集 (公社)日本薬学会 141年会 27P01 - 296 0918-9823 2021/03
  • Maho Tsubota; Kazuki Matsui; Maki Nakano; Rie Kajitani; Yuko Ishii; Ken Tomochika; Yuta Nishikawa; Saaya Fukushi; Ayumu Yamagata; Fumiko Sekiguchi; Takuya Okada; Naoki Toyooka; Atsufumi Kawabata
    European journal of pharmacology 892 173795 - 173795 2021/02
  • Maho Tsubota; Kazuki Matsui; Saaya Fukushi; Kyoko Okazaki; Fumiko Sekiguchi; Atsufumi Kawabata
    Biological & pharmaceutical bulletin 44 (3) 461 - 464 2021 
    T-Type Ca2+ channels (T-channels), particularly Cav3.2, are now considered as therapeutic targets for treatment of intractable pain including visceral pain. Among existing medicines, bepridil, a multi-channel blocker, used for treatment of arrhythmia and angina, and pimozide, a dopamine D2 receptor antagonist, known as a typical antipsychotic, have potent T-channel blocking activity. We thus tested whether bepridil and pimozide could suppress visceral pain in mice. Colonic and bladder pain were induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) and systemic administration of cyclophosphamide (CPA), respectively. Referred hyperalgesia was assessed by von Frey test, and colonic hypersensitivity to distension by a volume load with intracolonic water injection and spontaneous bladder pain were evaluated by observing nociceptive behaviors in conscious mice. The mice exhibited referred hyperalgesia and colonic hypersensitivity to distension on day 6 after TNBS treatment. Systemic administration of bepridil at 10-20 mg/kg or pimozide at 0.1-0.5 mg/kg strongly reduced the referred hyperalgesia on the TNBS-induced referred hyperalgesia and colonic hypersensitivity to distension. CPA treatment caused bladder pain-like nociceptive behavior and referred hyperalgesia, which were reversed by bepridil at 10-20 mg/kg or pimozide at 0.5-1 mg/kg. Our data thus suggest that bepridil and pimozide, existing medicines capable of blocking T-channels, are useful for treatment of colonic and bladder pain, and serve as seeds for the development of new medicines for visceral pain treatment.
  • Fumiko Sekiguchi; Atsufumi Kawabata
    International journal of molecular sciences 22 (1) 2020/12 
    Chemotherapy-induced peripheral neuropathy (CIPN), one of major dose-limiting side effects of first-line chemotherapeutic agents such as paclitaxel, oxaliplatin, vincristine, and bortezomib is resistant to most of existing medicines. The molecular mechanisms of CIPN have not been fully understood. High mobility group box 1 (HMGB1), a nuclear protein, is a damage-associated molecular pattern protein now considered to function as a pro-nociceptive mediator once released to the extracellular space. Most interestingly, HMGB1 plays a key role in the development of CIPN. Soluble thrombomodulin (TMα), known to degrade HMGB1 in a thrombin-dependent manner, prevents CIPN in rodents treated with paclitaxel, oxaliplatin, or vincristine and in patients with colorectal cancer undergoing oxaliplatin-based chemotherapy. In this review, we describe the role of HMGB1 and its upstream/downstream mechanisms in the development of CIPN and show drug candidates that inhibit the HMGB1 pathway, possibly useful for prevention of CIPN.
  • Shiori Tomita; Fumiko Sekiguchi; Yoshihito Kasanami; Katsuki Naoe; Maho Tsubota; Hidenori Wake; Masahiro Nishibori; Atsufumi Kawabata
    European journal of pharmacology 888 173587 - 173587 2020/12 
    Overexpression of Cav3.2 T-type Ca2+ channels in L4 dorsal root ganglion (DRG) participates in neuropathic pain after L5 spinal nerve cutting (L5SNC) in rats. The L5SNC-induced neuropathic pain also involves high mobility group box 1 (HMGB1), a damage-associated molecular pattern protein, and its target, the receptor for advanced glycation end-products (RAGE). We thus studied the molecular mechanisms for the L5SNC-induced Cav3.2 overexpression as well as neuropathic pain in rats by focusing on; 1) possible involvement of early growth response 1 (Egr-1), known to regulate transcriptional expression of Cav3.2, and ubiquitin-specific protease 5 (USP5) that protects Cav3.2 from proteasomal degradation, and 2) possible role of HMGB1/RAGE as an upstream signal. Protein levels of Cav3.2 as well as Egr-1 in L4 DRG significantly increased in the early (day 6) and persistent (day 14) phases of neuropathy after L5SNC, while USP5 protein in L4 DRG did not increase on day 6, but day 14. An anti-HMGB1-neutralizing antibody or a low molecular weight heparin, a RAGE antagonist, prevented the development of neuropathic pain and upregulation of Egr-1 and Cav3.2 in L4 DRG after L5SNC. L5SNC increased macrophages accumulating in the sciatic nerves, and the cytoplasm/nuclear ratio of immunoreactive HMGB1 in those macrophages. Our findings suggest that L5SNC-induced Cav3.2 overexpression in L4 DRG and neuropathic pain involves Egr-1 upregulation downstream of the macrophage-derived HMGB1/RAGE pathway, and that the delayed upregulation of USP5 might contribute to the persistent Cav3.2 overexpression and neuropathy.
  • Use of Transdermal Fentanyl and Elevated Gamma-glutamyl Transpeptidase Levels Are Associated with Increased Total Daily Dose of Opioid
    Miyamoto Tomoyoshi; Fujitani Masanori; Hatanaka Shigekatsu; Koizumi Yuichi; Kawabata Atsufumi
    Japanese Journal of Pharmaceutical Palliative Care and Sciences (一社)日本緩和医療薬学会 13 (4) 105 - 110 1882-9783 2020/12 [Refereed]
  • Maho Tsubota; Kazuki Matsui; Maki Nakano; Rie Kajitani; Yuko Ishii; Ken Tomochika; Yuta Nishikawa; Saaya Fukushi; Ayumu Yamagata; Fumiko Sekiguchi; Takuya Okada; Naoki Toyooka; Atsufumi Kawabata
    European journal of pharmacology 887 173576 - 173576 2020/11 
    Given the role of Cav3.2 isoform among T-type Ca2+ channels (T-channels) in somatic and visceral nociceptive processing, we analyzed the contribution of Cav3.2 to butyrate-induced colonic pain and nociceptor hypersensitivity in mice, to evaluate whether Cav3.2 could serve as a target for treatment of visceral pain in irritable bowel syndrome (IBS) patients. Mice of ddY strain, and wild-type and Cav3.2-knockout mice of a C57BL/6J background received intracolonic administration of butyrate twice a day for 3 days. Referred hyperalgesia in the lower abdomen was assessed by von Frey test, and colonic hypersensitivity to distension by a volume load or chemicals was evaluated by counting nociceptive behaviors. Spinal phosphorylated ERK was detected by immunohistochemistry. Cav3.2 knockdown was accomplished by intrathecal injection of antisense oligodeoxynucleotides. Butyrate treatment caused referred hyperalgesia and colonic hypersensitivity to distension in ddY mice, which was abolished by T-channel blockers and/or Cav3.2 knockdown. Butyrate also increased the number of spinal phosphorylated ERK-positive neurons following colonic distension in the anesthetized ddY mice. The butyrate-treated ddY mice also exhibited T-channel-dependent colonic hypersensitivity to intracolonic Na2S, known to enhance Cav3.2 activity, and TRPV1, TRPA1 or proteinase-activated receptor 2 (PAR2) agonists. Wild-type, but not Cav3.2-knockout, mice of a C57BL/6J background, after treated with butyrate, mimicked the T-channel-dependent referred hyperalgesia and colonic hypersensitivity in butyrate-treated ddY mice. Our study provides definitive evidence for an essential role of Cav3.2 in the butyrate-induced colonic pain and nociceptor hypersensitivity, which might serve as a target for treatment of visceral pain in IBS patients.
  • Kazuki Matsui; Yutaro Mukai; Kota Sakakura; Kyoichi Wada; Tsutomu Nakamura; Atsufumi Kawabata; Nobue Terakawa; Naoki Hayakawa; Kengo Kusano; Kouichi Hosomi; Satoshi Yokoyama; Mitsutaka Takada
    International journal of clinical pharmacology and therapeutics 59 (1) 63 - 70 2020/10 
    OBJECTIVE: Bepridil prolongs the QT interval and can induce torsade de pointes. Although increased bepridil concentration may be a primary cause of prolonged QT, the relationship between serum bepridil concentration and prolonged QT remains unclear. We investigated the relationship between serum bepridil concentration and the corrected QT (QTc) interval in patients treated with bepridil. MATERIALS AND METHODS: A retrospective study was performed at the National Cerebral and Cardiovascular Center in Japan. Patients with atrial fibrillation who were treated with bepridil from January 2014 to December 2015 were enrolled in the study. Serum bepridil concentrations and electrocardiogram data collected more than 21 days after the initiation of bepridil were used for analysis. RESULTS: A total of 60 patients were included in this study. There was a significant difference in mean QTc interval before and after initiation of bepridil (p < 0.0001). A significant relationship was observed between bepridil dose (p = 0.014) or serum bepridil concentration (p < 0.001) and QTc interval. Additionally, a significant relationship was observed between serum bepridil concentration and ΔQTc (p = 0.034). In the study, 4 patients developed QTc prolongation ≥ 500 ms after the initiation of bepridil. Serum bepridil concentration in this group was significantly higher compared with the group that did not display prolonged QTc (973 ± 651 vs. 526 ± 310 ng/mL, p = 0.01). CONCLUSION: This study revealed that the QTc interval was significantly associated with serum bepridil concentration. Serum bepridil concentration beyond a therapeutic range may be a critical risk factor for developing QTc prolongation.
  • Shiori Hiramoto; Maho Tsubota; Kaoru Yamaguchi; Kyoko Okazaki; Aya Sakaegi; Yuki Toriyama; Junichi Tanaka; Fumiko Sekiguchi; Hiroyasu Ishikura; Hidenori Wake; Masahiro Nishibori; Huy Du Nguyen; Takuya Okada; Naoki Toyooka; Atsufumi Kawabata
    Cells 9 (8) 2020/07 [Refereed]
     
    Cystitis-related bladder pain involves RAGE activation by HMGB1, and increased Cav3.2 T-type Ca2+ channel activity by H2S, generated by upregulated cystathionine-γ-lyase (CSE) in mice treated with cyclophosphamide (CPA). We, thus, investigated possible crosstalk between the HMGB1/RAGE and CSE/H2S/Cav3.2 pathways in the bladder pain development. Bladder pain (nociceptive behavior/referred hyperalgesia) and immuno-reactive CSE expression in the bladder were determined in CPA-treated female mice. Cell signaling was analyzed in urothelial T24 and macrophage-like RAW264.7 cells. The CPA-induced bladder pain was abolished by pharmacological inhibition of T-type Ca2+ channels or CSE, and genetic deletion of Cav3.2. The CPA-induced CSE upregulation, as well as bladder pain was prevented by HMGB1 inactivation, inhibition of HMGB1 release from macrophages, antagonists of RAGE or P2X4/P2X7 receptors, and N-acetylcysteine, an antioxidant. Acrolein, a metabolite of CPA, triggered ATP release from T24 cells. Adenosine triphosphate (ATP) stimulated cell migration via P2X7/P2X4, and caused HMGB1 release via P2X7 in RAW264.7 cells, which was dependent on p38MAPK/NF-κB signaling and reactive oxygen species (ROS) accumulation. Together, our data suggest that CPA, once metabolized to acrolein, causes urothelial ATP-mediated, redox-dependent HMGB1 release from macrophages, which in turn causes RAGE-mediated CSE upregulation and subsequent H2S-targeted Cav3.2-dependent nociceptor excitation, resulting in bladder pain.
  • Yuhei Irie; Maho Tsubota; Mariko Maeda; Shiori Hiramoto; Fumiko Sekiguchi; Hiroyasu Ishikura; Hidenori Wake; Masahiro Nishibori; Atsufumi Kawabata
    Journal of pharmacological sciences 143 (2) 112 - 116 2020/06 [Refereed]
     
    HMGB1, a nuclear protein, once released to the extracellular space, promotes somatic and visceral pain signals. We thus analyzed the role of HMGB1 in an intravesical substance P-induced bladder pain syndrome (BPS) mouse model. Intravesical administration of substance P caused referred hyperalgesia/allodynia in the lower abdomen and hindpaw without producing severe urothelial damage, which was prevented by an anti-HMGB1-neutralizing antibody, thrombomodulin α capable of inactivating HMGB1 and antagonists of RAGE or CXCR4. The HMGB1 inactivation or RAGE blockade also reversed the established bladder pain symptoms. HMGB1 and RAGE are thus considered to serve as therapeutic targets for BPS.
  • Ryuichi Tsujita; Maho Tsubota; Fumiko Sekiguchi; Atsufumi Kawabata
    British journal of pharmacology 178 (4) 798 - 812 2020/05 [Refereed]
     
    High-mobility group box 1 (HMGB1), a nuclear protein, once released to the extracellular space, facilitates pain signals as well as inflammation. Intraplantar or intraspinal application of HMGB1 elicits hyperalgesia/allodynia in rodents by activating the advanced glycosylation end-product specific receptor (receptor for advanced glycation end-products; RAGE) or Toll-like receptor 4 (TLR4). Endogenous HMGB1 derived from neurons, perineuronal cells or immune cells accumulating in the dorsal root ganglion or sensory nerves participates in somatic and visceral pain consisting of neuropathic and/or inflammatory components. Endothelial thrombomodulin (TM) and recombinant human soluble TM, TMα, markedly increase thrombin-dependent degradation of HMGB1, and systemic administration of TMα prevents and reverses various HMGB1-dependent pathological pain. Low MW compounds that directly inactivate HMGB1 or antagonize HMGB1-targeted receptors would be useful to reduce various forms of intractable pain. Thus, HMGB1 and its receptors are considered to serve as promising targets in developing novel agents to prevent or treat pathological pain.
  • 林 友典; 宮本 朋佳; 松岡 寛; 川畑 篤史
    日本臨床腫瘍薬学会雑誌 (一社)日本臨床腫瘍薬学会 15 211 - 211 2020/05
  • Kazuki Matsui; Yuka Terada; Maho Tsubota; Fumiko Sekiguchi; Atsufumi Kawabata
    Journal of pharmacological sciences 143 (1) 60 - 63 2020/05 [Refereed]
     
    TRPV1 is phosphorylated and functionally upregulated by protein kinases, and negatively regulated by phosphatases including calcineurin. Since the clinical use of calcineurin-inhibiting immunosuppressants is commonly associated with chronic diarrhea, we examined if tacrolimus, a calcineurin inhibitor, promotes TRPV1-dependent colonic hypersensitivity in mice. Intracolonic administration of capsaicin, a TRPV1 agonist, caused referred hyperalgesia in the lower abdomen, an effect prevented by capsazepine, a TRPV1 blocker. Tacrolimus accelerated the intracolonic capsaicin-induced referred hyperalgesia. Similarly, intracolonic capsaicin caused spinal ERK phosphorylation, a marker for nociceptor excitation, an effect promoted by tacrolimus. Thus, tacrolimus may aggravate TRPV1-related colonic pain accompanying irritable bowel syndrome.
  • 院内における簡易デンプン細粒調製法の確立 調剤用賦形剤として実用性向上を目指して
    吉川 知宏; 岡本 広世; 竹内 健太; 松岡 寛; 川畑 篤史; 長井 紀章
    日本薬学会年会要旨集 (公社)日本薬学会 140年会 27Y - pm01 0918-9823 2020/03
  • 院内における簡易デンプン細粒調製法の確立 調剤用賦形剤として実用性向上を目指して
    吉川 知宏; 岡本 広世; 竹内 健太; 松岡 寛; 川畑 篤史; 長井 紀章
    日本薬学会年会要旨集 (公社)日本薬学会 140年会 27Y - pm01 0918-9823 2020/03
  • Hiroyo Okamoto; Tomohiro Yoshikawa; Kenta Takeuchi; Saori Deguchi; Yuto Hatakenaka; Hiroshi Matsuoka; Atsufumi Kawabata; Noriaki Nagai
    Chemical & pharmaceutical bulletin 68 (6) 516 - 519 2020 [Refereed]
     
    Mohs paste is useful for controlling exudates from wounds and infections and is used to treat patients with inoperable skin tumors. Unfortunately, Mohs paste is difficult to preserve because its viscosity and stickiness increase dramatically immediately after preparation, resulting in decreased usability. In this study, the combined use of cryopreservation and kneading was shown to improve long-term storage of Mohs paste. At 25°C, Mohs pastes solidified rapidly, and viscosity reached approximately 700 Pa·s 5 h after preparation. In contrast, cryopreservation at -20°C attenuated hardening of Mohs pastes, and kneading also decreased viscosity. The viscosity of Mohs pastes cotreated with cryopreservation and kneading after 7 months of storage was <70 Pa·s. In addition, tissue invasion with these stored pastes was similar to freshly prepared Mohs paste. Results suggest that the combination of cryopreservation and kneading permits Mohs paste to be stored over extended periods, which may increase the utility of the paste for clinical use.
  • Tomonori Hayashi; Hinako Kawaguchi; Tsumugi Eifuku; Hiroshi Matsuoka; Atsufumi Kawabata; Noriaki Nagai
    Chemical & pharmaceutical bulletin 68 (9) 879 - 884 2020 [Refereed]
     
    The percutaneous absorption of a fentanyl (FEN)-patch is affected by various external factors including the volume of sebum secretion, which causes changes in the skin surface environment. In this study, we prepared a lard-based sebum-like secretion (SLS), and applied it to investigate the effect of different skin surface conditions on the drug penetration of a FEN-patch. In vitro work to test drug release using the Franz diffusion cell indicated that drug release was significantly suppressed by treatment with 5% SLS, which is equivalent to the amount of daily human sebum secretion. Conversely, in ex vivo experiments using rat skin, the amount of FEN that accumulated in the skin tissue of the 5% SLS-treated rats was higher in comparison with the non-SLS treated group. Furthermore, in vivo experiments indicated that the plasma FEN concentration in rats treated with the FEN-patch was significantly increased by treatment with 5% SLS. These results suggest that the sebum affected the release, accumulation, and absorption of FEN from the FEN-patch, and the FEN concentration in the blood was reflected by the balance of the suppression of drug release and the enhancement of drug accumulation in the skin with SLS.
  • Maho Tsubota; Ryotaro Fukuda; Yusuke Hayashi; Takaya Miyazaki; Shin Ueda; Rika Yamashita; Nene Koike; Fumiko Sekiguchi; Hidenori Wake; Shuji Wakatsuki; Yuka Ujiie; Toshiyuki Araki; Masahiro Nishibori; Atsufumi Kawabata
    Journal of neuroinflammation 16 (1) 199 - 199 2019/10 [Refereed]
     
    BACKGROUND: Macrophage-derived high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) protein, plays a key role in the development of chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel in rodents. Endothelial thrombomodulin (TM) promotes thrombin-induced degradation of HMGB1, and TMα, a recombinant human soluble TM, abolishes peripheral HMGB1-induced allodynia in mice. We thus examined whether HMGB1, particularly derived from macrophages, contributes to oxaliplatin-induced neuropathy in mice and analyzed the anti-neuropathic activity of the TM/thrombin system. METHODS: CIPN models were created by the administration of oxaliplatin in mice and rats, and the nociceptive threshold was assessed by von Frey test or paw pressure test. Macrophage-like RAW264.7 cells were stimulated with oxaliplatin in vitro. Proteins were detected and/or quantified by Western blotting, immunostaining, or enzyme-linked immunosorbent assay. RESULTS: Intraperitoneal administration of an anti-HMGB1-neutralizing antibody (AB) at 1 mg/kg prevented the oxaliplatin-induced allodynia in mice and rats. Antagonists of Toll-like receptor (TLR) 4, receptor for advanced glycation end products (RAGE) and CXCR4 among the HMGB1-targeted pro-nociceptive receptors, also mimicked the anti-neuropathic activity of AB in mice. Macrophage accumulation in the sciatic nerve was observed in mice treated with paclitaxel, but not oxaliplatin, and neither macrophage depletion nor inhibitors of macrophage activation affected oxaliplatin-induced allodynia. Oxaliplatin was 10- to 100-fold less potent than paclitaxel in releasing HMGB1 from macrophage-like RAW264.7 cells. Like AB, TMα at 10 mg/kg prevented the oxaliplatin-induced allodynia in mice as well as rats, an effect abolished by argatroban at 10 mg/kg, a thrombin inhibitor. The anti-neuropathic activity of TMα in oxaliplatin-treated mice was suppressed by oral anticoagulants such as warfarin at 1 mg/kg, dabigatran at 75 mg/kg, and rivaroxaban at 10 mg/kg, but not antiplatelet agents such as aspirin at 50 mg/kg and clopidogrel at 10 mg/kg. Repeated administration of the anticoagulants gradually developed neuropathic allodynia and elevated plasma HMGB1 levels in mice treated with a subeffective dose of oxaliplatin. CONCLUSIONS: Our data thus suggests a causative role of HMGB1 derived from non-macrophage cells in oxaliplatin-induced peripheral neuropathy and a thrombin-dependent anti-neuropathic activity of exogenous TMα and, most probably, endogenous TM.
  • Tomonori Hayashi; Yui Takashina; Hinako Kawaguchi; Tsumugi Eifuku; Hiroshi Matsuoka; Atsufumi Kawabata; Noriaki Nagai
    Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) Japanese Society of Pharmaceutical Health Care and Sciences 45 (7) 416 - 422 1346-342X 2019/07
  • Kazuki Matsui; Maho Tsubota; Saaya Fukushi; Nene Koike; Hiroshi Masuda; Yoshihito Kasanami; Takaya Miyazaki; Fumiko Sekiguchi; Tsuyako Ohkubo; Shigeru Yoshida; Yutaro Mukai; Akira Oita; Mitsutaka Takada; Atsufumi Kawabata
    Journal of pharmacological sciences 140 (3) 310 - 312 1347-8613 2019/07 [Refereed]
     
    We tested whether genetic deletion of Cav3.2 T-type Ca2+ channels abolishes hydrogen sulfide (H2S)-mediated pain signals in mice. In Cav3.2-expressing HEK293 cells, Na2S, an H2S donor, at 100 μM clearly increased Ba2+ currents, as assessed by whole-cell patch-clamp recordings. In wild-type C57BL/6 mice, intraplantar and intracolonic administration of Na2S evoked mechanical allodynia and visceral nociceptive behavior, respectively, which were abolished by TTA-A2, a T-type Ca2+ channel blocker. In Cav3.2-knockout mice of a C57BL/6 background, Na2S caused neither somatic allodynia nor colonic nociception. Our study thus provides definitive evidence for an essential role of Cav3.2 in H2S-dependent somatic and colonic pain.
  • Sachi Matsuda; Hiroyuki Nishikawa; Anna Fukatsu; Yuko Kurokawa; Maho Tsubota; Fumiko Sekiguchi; Shogo Tokuyama; Atsufumi Kawabata
    Journal of pharmacological sciences 140 (2) 193 - 196 1347-8613 2019/06 [Refereed]
     
    We tested whether NNC 55-0396 (NNC), a T-type calcium channel (T-channel) blocker, reduces the brain injury caused by middle cerebral artery occlusion and reperfusion (MCAO/R) in mice. NNC, administered i.c.v. before the occlusion, greatly reduced the MCAO/R-induced brain infarct and neurological dysfunctions, although it, given toward the end of occlusion, was less effective. Systemic administration of NNC before the occlusion also attenuated the infarct and neurological dysfunctions. Our data imply that blood-brain-barrier-permeable T-channel blockers such as NNC are capable of reducing MCAO/R-induced brain damage, and that T-channels are involved in neuronal damage induced by ischemia rather than reperfusion.
  • Tomoyoshi Miyamoto; Masanori Fujitani; Hiroki Fukuyama; Shigekatsu Hatanaka; Yuichi Koizumi; Atsufumi Kawabata
    Journal of palliative medicine 22 (5) 532 - 537 1096-6218 2019/05 [Refereed]
     
    Objective and Background: Survival predictions by subjective evaluations are important for end-stage patients. However, subjective evaluations based on experience are difficult. Therefore, we investigated whether the Glasgow prognostic score (GPS), prognostic nutritional index (PNI), and C-reactive protein (CRP)/albumin ratio (CRP/Alb ratio) calculated from the laboratory values of objective evaluations are useful for predicting survival times in end-stage patients. Methods: We retrospectively investigated the age, sex, death cause, CRP levels, Alb levels, and lymphocyte counts in 363 cancer and noncancer patients who died in the 12-month period between April 2015 and March 2016. A multivariate analysis was performed to calculate GPS, PNI, and the CRP/Alb ratio from laboratory values and adjusted for confounding factors. Results: PNI and CRP/Alb ratio exhibited negative and positive correlations with survival days, respectively. All GPS, PNI, and CRP/Alb ratio were useful to predict two to four remaining weeks. Interestingly, CRP/Alb ratio, but not GPS or PNI, was higher in patients with predicted short-term survival of zero to two weeks than in that of two to four weeks (odds ratio 2.32; 95% confidence interval 1.61-3.34). Discussion: These results suggest that the CRP/Alb ratio is an independent factor that is beneficial to predict short-term survival of within two weeks.
  • Maho Tsubota; Kenta Uebo; Koki Miki; Fumiko Sekiguchi; Akihiko Ishigami; Atsufumi Kawabata
    Biochemical and biophysical research communications 511 (3) 705 - 710 0006-291X 2019/04 [Refereed]
     
    Cav3.2 T-type Ca2+ channels are expressed in the primary afferents and play a pronociceptive role. The activity of Cav3.2 is enhanced by H2S, a gasotransmitter, and suppressed by ascorbic acid (vitamin C) through metal-catalyzed oxidation of the Zn2+-binding His191 in Cav3.2. Since rodents, but not humans, are capable of synthesizing ascorbic acid, the present study examined the role of ascorbic acid in nociceptive processing, using the mice lacking GNL/SMP30, an enzyme essential for ascorbic acid biosynthesis. Intraplantar and intracolonic administration of NaHS, an H2S donor, caused somatic allodynia and referred hyperalgesia, respectively, and repeated treatment with paclitaxel produced neuropathic allodynia in wild-type mice, all of which were suppressed by ascorbic acid or T-type Ca2+ channel blockers. Dietary ascorbic acid restriction caused dramatic decreases in plasma and tissue ascorbic acid levels in GNL/SMP30-knockout, but not wild-type, mice. The ascorbic acid restriction enhanced the somatic and visceral hypersensitivity following intraplantar and intracolonic NaHS, respectively, and paclitaxel-induced neuropathy in GNL/SMP30-knockout mice, while it had no such effect in wild-type mice. Together, our data unveil the critical role of ascorbic acid in regulating somatic and visceral pain sensitivity and support accumulating clinical evidence for the usefulness of ascorbic acid in pain management.
  • Shiori Tomita; Fumiko Sekiguchi; Tomoyo Deguchi; Takaya Miyazaki; Yuya Ikeda; Maho Tsubota; Shigeru Yoshida; Huy Du Nguyen; Takuya Okada; Naoki Toyooka; Atsufumi Kawabata
    Toxicology 413 33 - 39 0300-483X 2019/02 [Refereed]
     
    Bortezomib, a first-line agent for treatment of multiple myeloma, exhibits anticancer activity through proteasome inhibition. However, bortezomib-induced peripheral neuropathy (BIPN) is one of the most serious side effects. Since decreased proteasomal degradation of Cav3.2 T-type calcium channels in the primary afferents is involved in persistent pain, we investigated whether BIPN involves increased protein levels of Cav3.2 in mice. Six repeated i.p. administrations of bortezomib for 12 days developed persistent mechanical allodynia. Systemic administration of novel T-type calcium channel blockers, (2R/S)-6-prenylnaringenin and KTt-45, and of TTA-A2, the well-known blocker, reversed the BIPN. Ascorbic acid, known to block Cav3.2, but not Cav3.1 or 3.3, and silencing of Cav3.2 gene also suppressed BIPN. Protein levels of Cav3.2 in the dorsal root ganglion (DRG) at L4-L6 levels increased throughout days 1-21 after the onset of bortezomib treatment. Protein levels of USP5, a deubiquitinating enzyme that specifically inhibits proteasomal degradation of Cav3.2, increased in DRG on days 3-21, but not day 1, in bortezomib-treated mice. In DRG-derived ND7/23 cells, bortezomib increased protein levels of Cav3.2 and T-channel-dependent currents, as assessed by a patch-clamp method, but did not upregulate expression of Cav3.2 mRNA or USP5 protein. MG-132, another proteasome inhibitor, also increased Cav3.2 protein levels in the cultured cells. Given the previous evidence for USP5 induction following nociceptor excitation, our data suggest that BIPN involves the increased protein levels of Cav3.2 in nociceptors through inhibition of proteasomal degradation of Cav3.2 by bortezomib itself and then by USP5 that is upregulated probably in an activity-dependent manner.
  • HMGB1を標的とする化学療法誘発性末梢神経障害の予防
    川畑篤史; 坪田真帆; 関口富美子; 辻田隆一
    日本薬理学雑誌 in press 2019 [Invited]
  • Prenylflavanones as Novel T-Type Calcium Channel Blockers Useful for Pain Therapy
    SEKIGUCHI FumikoNguyen H-D; Okada T; Sekiguchi F; Tsubota M; Nishikawa H; Kawabata A; Toyooka N
    Nat Prod Commun 2019 1 - 11 2019 [Refereed]
  • Maho Tsubota; Atsufumi Kawabata
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica 154 (3) 128 - 132 0015-5691 2019 [Refereed]
     
    Hydrogen sulfide (H2S), an endogenous gasotransmitter, is generated from L-cysteine by 3 distinct enzymes including cystathionine-γ-lyase (CSE), and targets multiple molecules, thereby playing various roles in health and disease. H2S triggers or accelerates somatic pain and visceral nociceptive signals in the pancreas, colon and bladder by enhancing the activity of Cav3.2 T-type calcium channels. H2S also activates TRPA1, which participates in H2S-induced somatic pain signaling. However, Cav3.2 predominantly mediates colonic nociception by H2S, because genetic deletion of TRPA1 does not reduce H2S-induced colonic pain. The functional upregulation of the CSE/H2S/Cav3.2 system is involved in neuropathic pain and visceral pain accompanying pancreatitis and cystitis. Cav3.2 also appears to participate in irritable bowel syndrome (IBS), although the role of endogenous H2S generation by CSE in IBS is still open to question. In this review, we describe how H2S regulates pain signals, particularly by interacting with Cav3.2.
  • Fumiko Sekiguchi; Atsufumi Kawabata
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica 154 (3) 97 - 102 0015-5691 2019 [Refereed]
     
    Among voltage-gated Ca2+ channels, T-type Ca2+ channels, which are activated by low voltages, regulate neuronal excitability, spontaneous neurotransmitter release, hormone secretion, etc. and also participate in proliferation of distinct cancer cells. Among three isoforms of T-type Ca2+ channels, Cav3.2 is detectable in 100% of biopsy samples from prostate cancer patients. In general, prostate cancer cells are highly sensitive to androgen deprivation therapy, but often acquire hormone-therapy resistance. The androgen deprivation may trigger neuroendocrine (NE)-like differentiation of some prostate cancer cells. We have analyzed the expression and function of Cav3.2 in human prostate cancer LNCaP cells during NE-like differentiation. NE-like LNCaP cells overexpress Cav3.2 through the CREB/Egr-1 pathway and also cystathionine-γ-lyase (CSE), which generates H2S that enhances the channel activity of Cav3.2. H2S generated by upregulated CSE appears to enhance the activity of upregulated Cav3.2 after the differentiation. The enhanced Cav3.2 activity in NE-like cells may contribute to increased secretion of mitogenic factors essential for androgen-independent proliferation of surrounding prostate cancer cells. It is known that increased extracellular glucose levels enhance Cav3.2 activity through asparagine (N)-linked glycosylation of Cav3.2, which might contribute to diabetic neuropathy. We then found that high glucose accelerates the enhanced channel function and overexpression of Cav3.2 in NE-like LNCaP cells, which might be associated with clinical evidence for diabetes-related poor prognosis of prostate cancer and development of hormone therapy resistance. Thus, Cav3.2 is considered to play a role in the pathophysiology of prostate cancer, and may serve as a therapeutic target.
  • Atsufumi Kawabata; Maho Tsubota; Fumiko Sekiguchi; Ryuichi Tsujita
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica 154 (5) 236 - 240 0015-5691 2019 [Refereed]
     
    Chemotherapy-induced peripheral neuropathy (CIPN) considerably impairs cancer patients' QOL, and may lead to discontinuation of drug treatment of cancer. Currently, there is no effective strategy against CIPN. Therefore, it is an urgent issue to develop clinically available drugs that prevent or treat CIPN. We have shown that high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) molecule, plays an essential role in the development of CIPN. Most interestingly, thrombomodulin α, approved as a medicine for treatment of disseminated intravascular coagulation (DIC) in Japan, causes thrombin-dependent degradation of extracellular HMGB1 that is released in response to chemotherapeutics, and prevents CIPN. Thus, we expect that targeting HMGB1 or its receptors would lead to prevention of CIPN in cancer patients in near future.
  • Fumiko Sekiguchi; Risa Domoto; Kana Nakashima; Daichi Yamasoba; Hiroki Yamanishi; Maho Tsubota; Hidenori Wake; Masahiro Nishibori; Atsufumi Kawabata
    Neuropharmacology 141 201 - 213 0028-3908 2018/10 [Refereed]
     
    Given our recent evidence for the role of high mobility group box 1 (HMGB1) in chemotherapy-induced peripheral neuropathy (CIPN) in rats, we examined the origin of HMGB1 and the upstream and downstream mechanisms of HMGB1 release involved in paclitaxel-induced neuropathy in mice. Paclitaxel treatment developed mechanical allodynia in mice, as assessed by von Frey test, which was prevented by an anti-HMGB1-neutralizing antibody or thrombomodulin alfa capable of inactivating HMGB1. RAGE or CXCR4 antagonists, ethyl pyruvate or minocycline, known to inhibit HMGB1 release from macrophages, and liposomal clodronate, a macrophage depletor, prevented the paclitaxel-induced allodynia. Paclitaxel caused upregulation of RAGE and CXCR4 in the dorsal root ganglia and macrophage accumulation in the sciatic nerve. In macrophage-like RAW264.7 cells, paclitaxel evoked cytoplasmic translocation of nuclear HMGB1 followed by its extracellular release, and overexpression of CBP and PCAF, histone acetyltransferases (HATs), known to cause acetylation and cytoplasmic translocation of HMGB1, which were suppressed by ethyl pyruvate, N-acetyl-l-cysteine, an anti-oxidant, and SB203580 and PDTC, inhibitors of p38 MAP kinase (p38MAPK) and NF-κB, respectively. Paclitaxel increased accumulation of reactive oxygen species (ROS) and phosphorylation of p38MAPK, NF-κB p65 and I-κB in RAW264.7 cells. In mice, N-acetyl-l-cysteine or PDTC prevented the paclitaxel-induced allodynia. Co-culture of neuron-like NG108-15 cells or stimulation with their conditioned medium promoted paclitaxel-induced HMGB1 release from RAW264.7 cells. Our data indicate that HMGB1 released from macrophages through the ROS/p38MAPK/NF-κB/HAT pathway participates in the paclitaxel-induced peripheral neuropathy in mice, and unveils an emerging therapeutic avenue targeting a neuroimmune crosstalk in CIPN.
  • Huy Du Nguyen; Takuya Okada; Shun Kitamura; Sakura Yamaoka; Yamato Horaguchi; Yoshihito Kasanami; Fumiko Sekiguchi; Maho Tsubota; Shigeru Yoshida; Hiroyuki Nishikawa; Atsufumi Kawabata; Naoki Toyooka
    Bioorganic & medicinal chemistry 26 (15) 4410 - 4427 0968-0896 2018/08 [Refereed]
     
    Since 6-prenylnaringenin (6-PNG) was recently identified as a novel T-type calcium channel blocker with the IC50 value around 1 µM, a series of flavanone derivatives were designed, synthesized and subsequently evaluated for T-channel-blocking activity in HEK293 cells transfected with Cav3.2 T-type channels using a patch-clamp technique. As a result, several new flavanones blocked Cav3.2-dependent T-currents more potently than 6-PNG. In the synthesized compounds, 6-(3-ethylpent-2-enyl)-5,7-dihydroxy-2-(2-hydroxyphenyl)chroman-4-one 8j, 6-(3-ethylpent-2-enyl)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one 11b, 6-(2-cyclopentylideneethyl)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one 11d, and 6-(2-Cyclopentylethyl)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one 12c were more potent blocker than 6-PNG with the IC50 value of 0.39, 0.26, 0.46, and 0.50 µM, respectively. Among the above four derivatives, the compound 8j provided the best result in the in vivo experiments; i.e. systemic administration of 8j at the minimum dose completely restored neuropathic pain induced by partial sciatic nerve ligation in mice.
  • Fumiko Sekiguchi; Tomoyo Fujita; Takahiro Deguchi; Sakura Yamaoka; Ken Tomochika; Maho Tsubota; Sumire Ono; Yamato Horaguchi; Maki Ichii; Mio Ichikawa; Yumiko Ueno; Nene Koike; Tadatoshi Tanino; Huy Du Nguyen; Takuya Okada; Hiroyuki Nishikawa; Shigeru Yoshida; Tsuyako Ohkubo; Naoki Toyooka; Kazuya Murata; Hideaki Matsuda; Atsufumi Kawabata
    Neuropharmacology 138 232 - 244 0028-3908 2018/08 [Refereed]
     
    Since Cav3.2 T-type Ca2+ channels (T-channels) expressed in the primary afferents and CNS contribute to intractable pain, we explored T-channel-blocking components in distinct herbal extracts using a whole-cell patch-clamp technique in HEK293 cells stably expressing Cav3.2 or Cav3.1, and purified and identified sophoraflavanone G (SG) as an active compound from SOPHORAE RADIX (SR). Interestingly, hop-derived SG analogues, (2S)-6-prenylnaringenin (6-PNG) and (2S)-8-PNG, but not naringenin, also blocked T-channels; IC50 (μM) of SG, (2S)-6-PNG and (2S)-8-PNG was 0.68-0.75 for Cav3.2 and 0.99-1.41 for Cav3.1. (2S)-6-PNG and (2S)-8-PNG, but not SG, exhibited reversible inhibition. The racemic (2R/S)-6-PNG as well as (2S)-6-PNG potently blocked Cav3.2, but exhibited minor effect on high-voltage-activated Ca2+ channels and voltage-gated Na+ channels in differentiated NG108-15 cells. In mice, the mechanical allodynia following intraplantar (i.pl.) administration of an H2S donor was abolished by oral or i.p. SR extract and by i.pl. SG, (2S)-6-PNG or (2S)-8-PNG, but not naringenin. Intraperitoneal (2R/S)-6-PNG strongly suppressed visceral pain and spinal ERK phosphorylation following intracolonic administration of an H2S donor in mice. (2R/S)-6-PNG, administered i.pl. or i.p., suppressed the neuropathic allodynia induced by partial sciatic nerve ligation or oxaliplatin, an anti-cancer agent, in mice. (2R/S)-6-PNG had little or no effect on open-field behavior, motor performance or cardiovascular function in mice, and on the contractility of isolated rat aorta. (2R/S)-6-PNG, but not SG, was detectable in the brain after their i.p. administration in mice. Our data suggest that 6-PNG, a hop component, blocks T-channels, and alleviates neuropathic and visceral pain with little side effects.
  • Ryuichi Tsujita; Maho Tsubota; Yusuke Hayashi; Haruka Saeki; Fumiko Sekiguchi; Atsufumi Kawabata
    Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 13 (2) 179 - 188 1557-1890 2018/06 [Refereed]
     
    High mobility group box 1 (HMGB1), a nuclear protein, once released into the extracellular space under pathological conditions, plays a pronociceptive role in redox-dependent distinct active forms, all-thiol HMGB1 (at-HMGB1) and disulfide HMGB1 (ds-HMGB1), that accelerate nociception through the receptor for advanced glycation endproducts (RAGE) and Toll-like receptor 4 (TLR4), respectively. Thrombomodulin (TM), an endothelial membrane protein, and soluble TM, known as TMα, promote thrombin-mediated activation of protein C and also sequester HMGB1, which might facilitate thrombin degradation of HMGB1. The present study aimed at clarifying the role of thrombin in TMα-induced suppression of peripheral HMGB1-dependent allodynia in mice. Thrombin-induced degradation of at-HMGB1 and ds-HMGB1 was accelerated by TMα in vitro. Intraplantar (i.pl.) injection of bovine thymus-derived HMGB1 in an unknown redox state, at-HMGB1, ds-HMGB1 or lipopolysaccharide (LPS), known to cause HMGB1 secretion, produced long-lasting mechanical allodynia in mice, as assessed by von Frey test. TMα, when preadministered i.pl., prevented the allodynia caused by bovine thymus-derived HMGB1, at-HMGB1, ds-HMGB1 or LPS, in a dose-dependent manner. The TMα-induced suppression of the allodynia following i.pl. at-HMGB1, ds-HMGB1 or LPS was abolished by systemic preadministration of argatroban, a thrombin-inhibiting agent, and accelerated by i.pl. co-administered thrombin. Our data clearly indicate that TMα is capable of promoting the thrombin-induced degradation of both at-HMGB1 and ds-HMGB1, and suppresses the allodynia caused by either HMGB1 in a thrombin-dependent manner. Considering the emerging role of HMGB1 in distinct pathological pain models, the present study suggests the therapeutic usefulness of TMα for treatment of intractable and/or persistent pain.
  • Maho Tsubota; Yasumasa Okawa; Yuhei Irie; Mariko Maeda; Tomoka Ozaki; Fumiko Sekiguchi; Hiroyasu Ishikura; Atsufumi Kawabata
    Neuropharmacology 133 254 - 263 0028-3908 2018/05 [Refereed]
     
    Hydrogen sulfide (H2S) formed by cystathionine-γ-lyase (CSE) enhances the activity of Cav3.2 T-type Ca2+ channels, contributing to the bladder pain accompanying hemorrhagic cystitis caused by systemic administration of cyclophosphamide (CPA) in mice. Given clinical and fundamental evidence for the involvement of the substance P/NK1 receptor systems in bladder pain syndrome (BPS)/interstitial cystitis (IC), we created an intravesical substance P-induced bladder pain model in mice and analyzed the possible involvement of the CSE/Cav3.2 pathway. Bladder pain/cystitis was induced by i.p. CPA or intravesical substance P in female mice. Bladder pain was evaluated by counting nociceptive behavior and by detecting referred hyperalgesia in the lower abdomen and hindpaw. The isolated bladder tissue was weighed to estimate bladder swelling and subjected to histological observation and Western blotting. Intravesical substance P caused profound referred hyperalgesia accompanied by little bladder swelling or edema 6-24 h after the administration, in contrast to i.p. CPA-induced nociceptive behavior/referred hyperalgesia with remarkable bladder swelling/edema and urothelial damage. The bladder pain and/or cystitis symptoms caused by substance P or CPA were prevented by the NK1 receptor antagonist. CSE in the bladder was upregulated by substance P or CPA, and the NK1 antagonist prevented the CPA-induced CSE upregulation. A CSE inhibitor, a T-type Ca2+ channel blocker and gene silencing of Cav3.2 abolished the intravesical substance P-induced referred hyperalgesia. The intravesical substance P-induced pain in mice is useful as a model for nonulcerative BPS, and involves the activation of the NK1 receptor/CSE/H2S/Cav3.2 cascade.
  • Tomoka Ozaki; Maho Tsubota; Fumiko Sekiguchi; Atsufumi Kawabata
    Clinical and experimental pharmacology & physiology 45 (4) 355 - 361 0305-1870 2018/04 [Refereed]
     
    Hydrogen sulfide (H2 S) is generated from l-cysteine by multiple enzymes including cystathionine-γ-lyase (CSE), and promotes nociception by targeting multiple molecules such as Cav 3.2 T-type Ca2+ channels. Bladder pain accompanying cyclophosphamide (CPA)-induced cystitis in mice has been shown to involve the functional upregulation of the CSE/H2 S/Cav 3.2 pathway. Therefore, we investigated whether NF-κB, as an upstream signal of the CSE/H2 S system, contributes to bladder pain in mice with CPA-induced cystitis. Bladder pain-like nociceptive behaviour was observed in CPA-treated mice, and referred hyperalgesia was evaluated by the von Frey test. Isolated bladder weights were assessed to estimate bladder swelling, and protein levels were measured by Western blotting. CPA, administered intraperitoneally, induced nociceptive behaviour, referred hyperalgesia and increased bladder weights in mice. β-Cyano-l-alanine, a reversible selective CSE inhibitor, prevented CPA-induced nociceptive behaviour, referred hyperalgesia, and, in part, increases in bladder weight. CPA markedly increased phosphorylated NF-κB p65 levels in the bladder, an effect that was prevented by pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor. PDTC and curcumin, which inhibits NF-κB signals, abolished CPA-induced nociceptive behaviour, referred hyperalgesia and, in part, increases in bladder weight. CPA caused the overexpression of CSE in the bladder, and this was prevented by PDTC or curcumin. The CPA-induced activation of NF-κB signals appeared to cause CSE overexpression in the bladder, contributing to bladder pain and in part swelling, possibly through H2 S/Cav 3.2 signaling. Therefore, NF-κB-inhibiting compounds including curcumin may be useful for the treatment of cystitis-related bladder pain.
  • Tomoka Ozaki; Junki Matsuoka; Maho Tsubota; Shiori Tomita; Fumiko Sekiguchi; Takeshi Minami; Atsufumi Kawabata
    Toxicology 393 102 - 112 0300-483X 2018/01 [Refereed]
     
    Cav3.2 T-type Ca2+ channel activity is suppressed by zinc that binds to the extracellular histidine-191 of Cav3.2, and enhanced by H2S that interacts with zinc. Cav3.2 in nociceptors is upregulated in an activity-dependent manner. The enhanced Cav3.2 activity by H2S formed by the upregulated cystathionine-γ-lyase (CSE) is involved in the cyclophosphamide (CPA)-induced cystitis-related bladder pain in mice. We thus asked if zinc deficiency affects the cystitis-related bladder pain in mice by altering Cav3.2 function and/or expression. Dietary zinc deficiency for 2 weeks greatly decreased zinc concentrations in the plasma but not bladder tissue, and enhanced the bladder pain/referred hyperalgesia (BP/RH) following CPA at 200mg/kg, a subeffective dose, but not 400mg/kg, a maximal dose, an effect abolished by pharmacological blockade or gene silencing of Cav3.2. Acute zinc deficiency caused by systemic N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylendiamine (TPEN), a zinc chelator, mimicked the dietary zinc deficiency-induced Cav3.2-dependent promotion of BP/RH following CPA at 200mg/kg. CPA at 400mg/kg alone or TPEN plus CPA at 200mg/kg caused Cav3.2 overexpression accompanied by upregulation of Egr-1 and USP5, known to promote transcriptional expression and reduce proteasomal degradation of Cav3.2, respectively, in the dorsal root ganglia (DRG). The CSE inhibitor, β-cyano-l-alanine, prevented the BP/RH and upregulation of Cav3.2, Egr-1 and USP5 in DRG following TPEN plus CPA at 200mg/kg. Together, zinc deficiency promotes bladder pain accompanying CPA-induced cystitis by enhancing function and expression of Cav3.2 in nociceptors, suggesting a novel therapeutic avenue for treatment of bladder pain, such as zinc supplementation.
  • Fumiko Sekiguchi; Maho Tsubota; Atsufumi Kawabata
    Biological & pharmaceutical bulletin 41 (8) 1127 - 1134 0918-6158 2018 [Refereed]
     
    Voltage-gated calcium channels (VGCCs) are classified into high-voltage-activated (HVA) channels and low-voltage-activated channels consisting of Cav3.1-3.3, known as T ("transient")-type VGCC. There is evidence that certain types of HVA channels are involved in neurogenic inflammation and inflammatory pain, in agreement with reports indicating the therapeutic effectiveness of gabapentinoids, ligands for the α2δ subunit of HVA, in treating not only neuropathic, but also inflammatory, pain. Among the Cav3 family members, Cav3.2 is abundantly expressed in the primary afferents, regulating both neuronal excitability at the peripheral terminals and spontaneous neurotransmitter release at the spinal terminals. The function and expression of Cav3.2 are modulated by a variety of inflammatory mediators including prostanoids and hydrogen sulfide (H2S), a gasotransmitter. The increased activity of Cav3.2 by H2S participates in colonic, bladder and pancreatic pain, and regulates visceral inflammation. Together, VGCCs are involved in inflammation and inflammatory pain, and Cav3.2 T-type VGCC is especially a promising therapeutic target for the treatment of visceral inflammatory pain in patients with irritable bowel syndrome, interstitial cystitis/bladder pain syndrome, pancreatitis, etc., in addition to neuropathic pain.
  • Yusuke Hayashi; Ryuichi Tsujita; Maho Tsubota; Haruka Saeki; Fumiko Sekiguchi; Goichi Honda; Atsufumi Kawabata
    Biochemical and biophysical research communications 495 (1) 634 - 638 0006-291X 2018/01 [Refereed]
     
    Thrombomodulin (TM), an endothelial protein with anti-coagulant activity, is composed of 5 domains, D1-D5. Recombinant human soluble TM (TMα) consisting of D1-D3, which is generated in CHO cells, suppresses inflammatory and nociceptive signals by inactivating high mobility group box 1 (HMGB1), one of damage-associated molecular patterns. TMα sequesters HMGB1 with the lectin-like D1 and promotes its degradation by thrombin binding to the EGF-like D2. We prepared TM's D123, D1 and D2 by the protein expression system of yeast, and evaluated their effects on HMGB1 degradation in vitro and on the allodynia caused by HMGB1 in distinct redox forms in mice in vivo. TMα and TM's D123, but not D1, promoted the thrombin-dependent degradation of all-thiol (at-HMGB1) and disulfide HMGB1 (ds-HMGB1), an effect mimicked by TM's D2, though to a lesser extent. Intraplantar administration of TMα and TM's D123, but not D1, D2 or D1 plus D2, strongly prevented the mechanical allodynia caused by intraplantar at-HMGB1, ds-HMGB1 or lipopolysaccharide in mice. Our data suggest that, apart from the role of D3, TMα and TM's D123 require both lectin-like D1 capable of sequestering HMGB1 and EGF-like D2 responsible for thrombin-dependent degradation of HMGB1, in abolishing the allodynia caused by exogenous or endogenous HMGB1.
  • Maho Tsubota; Tomoka Ozaki; Yuko Hayashi; Yasumasa Okawa; Ayaka Fujimura; Fumiko Sekiguchi; Hiroyuki Nishikawa; Atsufumi Kawabata
    Journal of pharmacological sciences 136 (1) 46 - 49 1347-8613 2018/01 [Refereed]
     
    We studied the pronociceptive role of proteinase-activated receptor-2 (PAR2) in mouse bladder. In female mice, intravesical infusion of the PAR2-activating peptide, SLIGRL-amide (SL), caused delayed mechanical hypersensitivity in the lower abdomen, namely 'referred hyperalgesia', 6-24 h after the administration. The PAR2-triggered referred hyperalgesia was prevented by indomethacin or a selective TRPV1 blocker, and restored by a T-type Ca2+ channel blocker. In human urothelial T24 cells, SL caused delayed prostaglandin E2 production and COX-2 upregulation. Our data suggest that luminal PAR2 stimulation in the bladder causes prostanoid-dependent referred hyperalgesia in mice, which involves the activation of TRPV1 and T-type Ca2+ channels.
  • Yuhei Irie; Maho Tsubota; Hiroyasu Ishikura; Fumiko Sekiguchi; Yuka Terada; Toshifumi Tsujiuchi; Keyue Liu; Masahiro Nishibori; Atsufumi Kawabata
    JOURNAL OF NEUROIMMUNE PHARMACOLOGY SPRINGER 12 (4) 693 - 707 1557-1890 2017/12 [Refereed]
     
    Extracellular high mobility group box 1 (HMGB1) activates the receptor for advanced glycation end products (RAGE) or Toll-like receptor 4 (TLR4) and forms a heterocomplex with CXCL12 that strongly activates CXCR4, promoting inflammatory and pain signals. In the present study, we investigated the role of HMGB1 in pancreatic pain accompanying cerulein-induced acute pancreatitis in mice. Abdominal referred hyperalgesia accompanying acute pancreatitis occurred within 1 h after 6 hourly injections of cerulein. The anti-HMGB1 neutralizing antibody or recombinant human soluble thrombomodulin (rhsTM), known to inactivate HMGB1, abolished the cerulein-induced referred hyperalgesia, but not pancreatitis itself. Plasma or pancreatic HMGB1 levels did not change, but macrophage infiltration into the pancreas occurred 1 h after cerulein treatment. Minocycline, a macrophage/microglia inhibitor, ethyl pyruvate that inhibits HMGB1 release from macrophages, or liposomal clodronate that depletes macrophages prevented the referred hyperalgesia, but not pancreatitis. Antagonists of RAGE or CXCR4, but not TLR4, strongly suppressed the cerulein-induced referred hyperalgesia, but not pancreatitis. Upregulation of RAGE, CXCR4 and CXCL12, but not TLR4, were detected in the pancreas 1 h after cerulein treatment. Our data suggest that HMGB1 regionally secreted by macrophages mediates pancreatic pain by targeting RAGE and CXCL12/CXCR4 axis in the early stage of acute pancreatitis.
  • Functional regulation of ion channels by H2S and its pathological impact
    SEKIGUCHI Fumiko; KAWABATA Atsufumi
    硫酸と工業 70 (5) 61 - 70 2017/05 [Invited]
  • Sekiguchi Fumiko; Noda Sayuri; Ono Sumire; Murata Kazuya; Matsuda Hideaki; Huy Du Nguyen; Toyooka Naoki; Harada Narinobu; Ito Yukari; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES 133 (3) S176  1347-8613 2017/03 [Refereed]
  • Yuka Terada; Kyoichi Wada; Sachi Matsuda; Takeshi Kuwahara; Atsufumi Kawabata; Mitsutaka Takada; Takuya Watanabe; Seiko Nakajima; Takuma Sato; Osamu Seguchi; Masanobu Yanase; Norihide Fukushima; Takeshi Nakatani
    INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS DUSTRI-VERLAG DR KARL FEISTLE 55 (1) 1 - 8 0946-1965 2017/01 [Refereed]
     
    Objective: To evaluate circadian changes in everolimus (EVL) pharmacokinetics and to identify the time point of blood sampling with the strongest correlation with the area under the blood concentration time curve (AUC) of EVL in heart transplant patients. Methods: Heart transplant patients receiving the same dose of EVL twice a day were reviewed. In 28 patients enrolled, whole blood samples were collected before (C-0), and 1, 2, 4, 6, 8, and 12 hours after each administration of EVL. Blood concentrations of EVL were compared between active (9:00 AM to 9:00 PM) and resting periods (9:00 PM to 9:00 AM). Results: AUC(0-4h), peak concentration (C-max), C-max/minimum concentration, and peak-trough fluctuation in the resting period were significantly lower than those in the active period (p = 0.008, 0.017, 0.022, and 0.011, respectively). Halflife and mean residence time were significantly longer in the resting period than in the active period (p = 0.002 and 0.002, respectively). AUC(0-12h) in the active period was similar (p = 0.154) and correlated with that in the resting period (r(2) = 0.93). Two-point blood samplings, C-0 and C-2, correlated more strongly with AUC(0-12h) for EVL, compared with C-0 alone (0.92 vs. 0.79, respectively, for r(2) in the active period). Conclusions: EVL pharmacokinetics showed circadian changes, suggesting delayed absorption and decreased metabolic activity at rest. However, the circadian changes did not affect AUC(0-12h). A 2-time-point model that included C-0 and C-2 was more accurate for predicting the AUC(0-12h) of EVL than C-0 alone in heart transplant patients.
  • Kazuki Fukami; Fumiko Sekiguchi; Atsufumi Kawabata
    PHARMACOLOGY KARGER 99 (3-4) 196 - 203 0031-7012 2017 [Refereed]
     
    Background: Hydrogen sulfide (H2S), a gasotransmitter, is generated from L-cysteine by mainly 3 enzymes, cystathionine-Upsilon-lyase (CSE), cystathionine-beta-synthase, and 3-mercaptopyruvate sulfurtransferase in cooperation with cysteine aminotransferase. The H2S-forming enzymes, particularly CSE, are overexpressed under the pathological conditions such as inflammation, neuronal or neuroendocrine differentiation and cancer development. Given that Ca(v)3.2 T-type Ca2+ channels mediate some of the biological activity of H2S, we focus on the role of the H2S/Ca(v)3.2 pathway in regulating the neuronal and neuroendocrine function. Summary: In the neuronal system, H2S regulates the activity of various ion channels including Ca(v)3.2. Exogenous and endogenous H2S enhances the Ca(v)3.2 channel activity, promoting somatic and visceral pain signaling. The H2S/Ca(v)3.2 pathway also facilitates neuritogenesis or neuronal differentiation. Interestingly, endogenous H2S formed by CSE regulates secretory function by enhancing Ca(v)3.2 channel activity in neuroendocrine-differentiated prostate cancer cells or carotid glomus cells. Key Messages: The H2S/Ca(v)3.2 pathway may serve as therapeutic targets for treatment of intractable pain, neuronal injury, androgen-independent prostate cancer, cardiovascular diseases, etc. (C) 2016 S. Karger AG, Basel
  • Tomoyoshi Miyamoto; Yoshinori Funakami; Erika Kawashita; Shiori Tomita; Ai Nomura; Nanako Sugimoto; Haruka Saeki; Takaya Miyazaki; Maho Tsubota; Seiji Ichida; Atsufumi Kawabata
    PHARMACOLOGY KARGER 99 (3-4) 172 - 178 0031-7012 2017 [Refereed]
     
    Lipopolysaccharide (LPS) induces hyperthermia accompanied by various other systemic inflammatory symptoms. The rodents exposed to repeated cold (RC) stress according to a specific schedule are useful as experimental models for autonomic imbalance or fibromyalgia. It is now proven that RC-stressed mice exhibit tolerance to LPS, we examined thermal responses to LPS challenge in RC-stressed mice by monitoring core temperature using the telemetry system. Systemic administration of LPS caused bimodal hyperthermic responses in RC-stressed and unstressed mice. The magnitude of the LPS-induced hyperthermia was greater in RC-stressed mice than in unstressed mice. The RC stress-induced enhancement of hyperthermic responses to LPS was abolished by pretreatment with diclofenac, which is a cyclooxygenase (COX) inhibitor. LPS did not significantly increase COX-2 protein levels in the lung or hypothalamus of RC-stressed or unstressed mice. RC stress did not alter baseline serum corticosterone levels or their increases in response to LPS challenge. These results suggest that RC stress enhances the susceptibility of mice to LPS challenge, leading to greater prostanoid-dependent hyperthermia, which might contribute to tolerance to LPS in RC-stressed mice. (C) 2016 S. Karger AG, Basel.
  • Tomoyoshi Miyamoto; Yoshinori Funakami; Erika Kawashita; Ai Nomura; Nanako Sugimoto; Haruka Saeki; Maho Tsubota; Seiji Ichida; Atsufumi Kawabata
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 40 (1) 11 - 16 0918-6158 2017/01 [Refereed]
     
    The rodents exposed to repeated cold stress according to a specific schedule, known as specific alternation of rhythm in temperature (SART), exhibit autonomic imbalance, and is now used as an experimental model of fibromyalgia. To explore the susceptibility of SART-stressed animals to novel acute stress, we tested whether exposure of mice to SART stress for 1 week alters the extent of acute restraint stress-induced hyperthermia. Mice were subjected to 7-d SART stress sessions; i.e., the mice were alternately exposed to 24 and 4 degrees C at 1-h intervals during the daytime (09:00-16:00) and kept at 4 degrees C overnight (16:00-09:00). SART-stressed and unstressed mice were exposed to acute restraint stress for 20-60 min, during which rectal temperature was monitored. Serum corticosterone levels were measured before and after 60-min exposure to restraint stress. SART stress itself did not alter the body temperature or serum corticosterone levels in mice. Acute restraint stress increased the body temperature and serum corticosterone levels, both responses being greater in SART-stressed mice than unstressed mice. The enhanced hyperthermic responses to acute restraint stress in SART-stressed mice were significantly attenuated by SR59230A, a beta(3) adrenoceptor antagonist, but unaffected by diazepam, an anxiolytic, mifepristone, a glucocorticoid receptor antagonist, or indomethacin, a cyclooxygenase inhibitor. These results suggest that SART stress enhances the susceptibility of mice to acute restraint stress, characterized by increased hyperthermia and corticosterone secretion, and that the increased hyperthermic responses to acute stress might involve accelerated activation of sympathetic beta(3) adrenoceptors, known to regulate non-shivering thermogenesis in the brown adipose tissue.
  • Kazuki Fukami; Erina Asano; Mai Ueda; Fumiko Sekiguchi; Shigeru Yoshida; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 133 (1) 57 - 60 1347-8613 2017/01 [Refereed]
     
    Given that Ca(v)3.2 T-type Ca2+ channels were functionally regulated by asparagine (N)-linked glycosylation, we examined effects of high glucose on the function of Ca(v)3.2, known to regulate secretory function, in neuroendocrine-like differentiated prostate cancer LNCaP cells. High glucose accelerated the increased channel function and overexpression of Ca(v)3.2 during neuroendocrine differentiation, the former prevented by enzymatic inhibition of N-glycosylation and cleavage of N-glycans. Hyperglycemia thus appears to induce N-linked glycosylation-mediated functional upregulation and overexpression of Ca(v)3.2 in neuroendocrine-like differentiated prostate cancer cells. (C) 2017 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
  • Yuka Terada; Maho Tsubota; Hiiragi Sugo; Kohei Wakitani; Fumiko Sekiguchi; Kyoichi Wada; Mitsutaka Takada; Akira Oita; Atsufumi Kawabata
    PHARMACOLOGY KARGER 99 (5-6) 281 - 285 0031-7012 2017 [Refereed]
     
    Transient receptor potential vanilloid-1 (TRPV1) expressed in nociceptors is directly phosphorylated and activated by protein kinase C, and involved in the signaling of pancreatic pain. On the other hand, Ca(v)3.2 T-type Ca2+ channels expressed in nociceptors are functionally upregulated by phosphorylation with protein kinase A and also play a role in pancreatitis-related pain. Calcineurin, a phosphatase, negatively regulates various channel functions including TRPV1, and calcineurin inhibitor-induced pain syndrome by tacrolimus, a calcineurin inhibitor, used as an immunosuppressant, has been a clinical problem. We thus examined the effect of tacrolimus on pancreatitis-related pain in mice. Repeated treatment with cerulein caused referred hyperalgesia accompanying acute pancreatitis, which was unaffected by tacrolimus. Pancreatitis-related symptoms disappeared in 24 h, whereas the referred hyperalgesia recurred following the administration of tacrolimus, which was abolished by the blockers of TRPV1 but not T-type Ca2+ channels. Thus, tacrolimus appears to cause the TRPV1-dependent relapse of pancreatitis-related pain, suggesting the involvement of calcineurin in the termination of pancreatic pain. (C) 2017 S. Karger AG, Basel
  • Maho Tsubota; Tomoyoshi Miyamoto; Saki Hiruma; Haruka Saeki; Takaya Miyazaki; Fumiko Sekiguchi; Yoshinori Funakami; Atsufumi Kawabata
    PHARMACOLOGY KARGER 99 (5-6) 286 - 290 0031-7012 2017 [Refereed]
     
    We examined the effect of repeated cold (RC) stress on cyclophosphamide (CPA)-induced cystitis/bladder pain in mice, in relation to macrophage activity. CPA, given i.p. at 400 mg/kg, caused bladder pain symptoms accompanying cystitis in both unstressed and RC-stressed mice, which were prevented by the macrophage inhibitor minocycline. A low dose, that is, 200 mg/kg, of CPA still produced bladder pain symptoms in unstressed but not RC-stressed mice. Lipopoly-saccharide-induced cytokine production in peritoneal macrophages from RC-stressed mice was less than that from unstressed mice. Thus, RC stress appears to reduce CPA-induced bladder pain in mice, which may be associated with the decreased macrophage activity. (C) 2017 S. Karger AG, Basel
  • Fumiko Sekiguchi; Yuma Kawara; Maho Tsubota; Eri Kawakami; Tomoka Ozaki; Yudai Kawaishi; Shiori Tomita; Daiki Kanaoka; Shigeru Yoshida; Tsuyako Ohkubo; Atsufumi Kawabata
    PAIN LIPPINCOTT WILLIAMS & WILKINS 157 (8) 1655 - 1665 0304-3959 2016/08 [Refereed]
     
    T-type Ca2+ channels (T channels), particularly Ca(v)3.2 among the 3 isoforms, play a role in neuropathic and visceral pain. We thus characterized the effects of RQ-00311651 (RQ), a novel T-channel blocker, in HEK293 cells transfected with human Ca(v)3.1 or Ca(v)3.2 by electrophysiological and fluorescent Ca2+ signaling assays, and also evaluated the antiallodynic/antihyperalgesic activity of RQ in somatic, visceral, and neuropathic pain models in rodents. RQ-00311651 strongly suppressed T currents when tested at holding potentials of -65 similar to - 260 mV, but not -80 mV, in the Ca(v)3.1- or Ca(v)3.2-expressing cells. RQ-00311651 also inhibited high K+-induced Ca2+ signaling in those cells. In mice, RQ, administered intraperitoneally (i.p.) at 5 to 20 mg/kg or orally at 20 to 40 mg/kg, significantly suppressed the somatic hyperalgesia and visceral pain-like nociceptive behavior/referred hyperalgesia caused by intraplantar and intracolonic administration of NaHS or Na2S, H2S donors, respectively, which involve the enhanced activity of Ca(v)3.2 channels. RQ-00311651, given i.p. at 5 to 20 mg/kg, exhibited antiallodynic or antihyperalgesic activity in rats with spinal nerve injury-induced neuropathy or in rats and mice with paclitaxel-induced neuropathy. Oral and i.p. RQ at 10 to 20 mg/kg also suppressed the visceral nociceptive behavior and/or referred hyperalgesia accompanying cerulein-induced acute pancreatitis and cyclophosphamide-induced cystitis in mice. The analgesic and antihyperalgesic/antiallodynic doses of oral and i.p. RQ did not significantly affect the locomotor activity and motor coordination. Together, RQ is considered a state-dependent blocker of Ca(v)3.1/Ca(v)3.2 T channels and may serve as an orally available analgesic for treatment of neuropathic and inflammatory pain including distinct visceral pain with minimum central side effects.
  • Terada Yuka; Wada Kyoichi; Matsuda Sachi; Kuwahara Takeshi; Kawabata Atsufumi; Takada Mitsutaka; Hisamatsu Eriko; Sunami Haruki; Nakajima Seiko; Sato Takuma; Seguchi Osamu; Yanase Masanobu; Fukushima Norihide; Nakatani Takeshi
    TRANSPLANTATION 100 (7) S825 - S826 0041-1337 2016/07 [Refereed]
  • Takeshi Nishida; Maho Tsubota; Yudai Kawaishi; Hiroki Yamanishi; Natsuki Kamitani; Fumiko Sekiguchi; Hiroyasu Ishikura; Keyue Liu; Masahiro Nishibori; Atsufumi Kawabata
    TOXICOLOGY ELSEVIER IRELAND LTD 365 48 - 58 0300-483X 2016/07 [Refereed]
     
    Given that high mobility group box 1 (HMGB1), a nuclear protein, once released to the extracellular space, promotes nociception, we asked if inactivation of HMGB1 prevents or reverses chemotherapy-induced painful neuropathy in rats and also examined possible involvement of Toll-like receptor 4 (TLR4) and the receptor for advanced glycation endproduct (RAGE), known as targets for HMGB1. Painful neuropathy was produced by repeated i.p. administration of paclitaxel or vincristine in rats. Nociceptive threshold was determined by the paw pressure method and/or von Frey test in the hindpaw. Tissue protein levels were determined by immunoblotting. Repeated i.p. administration of the anti-HMGB1-neutralizing antibody or recombinant human soluble thrombomodulin (rhsTM), known to inactivate HMGB1, prevented the development of hyperalgesia and/or allodynia induced by paclitaxel or vincristine in rats. A single i.p. or intraplantar (i.pl.) administration of the antibody or rhsTM reversed the chemotherapy induced neuropathy. A single i.pl. administration of a TLR4 antagonist or low molecular weight heparin, known to inhibit RAGE, attenuated the hyperalgesia caused by i.pl. HMGB1 and also the chemotherapy induced painful neuropathy. Paclitaxel or vincristine treatment significantly decreased protein levels of HMGB1 in the dorsal root ganglia, but not sciatic nerves. HMGB1 thus participates in both development and maintenance of chemotherapy-induced painful neuropathy, in part through RAGE and TLR4. HMGB1 inactivation is considered useful to prevent and treat the chemotherapy-induced painful neuropathy. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Fumiko Sekiguchi; Teruki Sekimoto; Ayaka Ogura; Atsufumi Kawabata
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 39 (5) 887 - 890 0918-6158 2016/05 [Refereed]
     
    Hydrogen sulfide (H2S), the third gasotransmitter, is endogenously generated by certain H2S synthesizing enzymes, including cystathionine-gamma-lyase (CSE) and cystathionine-beta-synthase (CBS) from L-cysteine in the mammalian body. Several studies have shown that endogenous and exogenous H2S affects the proliferation of cancer cells, although the effects of H2S appear to vary with cell type, being either promotive or suppressive. In the present study, we determined whether endogenously formed H2S regulates proliferation in human gastric cancer AGS cells. CSE, but not CBS, was expressed in AGS cells. CSE inhibitors, DL-propargylglycine (PPG) and beta-cyano-L-alanine (BCA), significantly suppressed the proliferation of AGS cells in a concentration-dependent manner. CSE inhibitors did not increase lactate dehydrogenase (LDH) release in the same concentration range. The inhibitory effects of PPG and BCA on cell proliferation were reversed by repetitive application of NaHS, a donor of H2S. Interestingly, nuclear condensation and fragmentation were detected in AGS cells treated with PPG or BCA. These results suggest that endogenous H2S produced by CSE may contribute to the proliferation of gastric cancer AGS cells, most probably through anti-apoptotic actions.
  • Ono Sumire; Yamaoka Sakura; Sekiguchi Fumiko; Ichii Maki; Fujita Tomoyo; Deguchi Takahiro; Tsubota Maho; Nishikawa Hiroyuki; Yoshida Shigeru; Murata Kazuya; Matsuda Hideaki; Toyooka Naoki; Ohkubo Tsuyako; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 130 (3) S146 - S146 1347-8613 2016/03 [Refereed]
  • Irie Yuhei; Tsubota Maho; Sekiguchi Fumiko; Ishikura Hiroyasu; Nishibori Masahiro; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES 130 (3) S81  1347-8613 2016/03 [Refereed]
  • Tomita Shiori; Shikimi Shiyu; Sekiguchi Fumiko; Tsubota Maho; Shirai Akihiro; Nishibori Masahiro; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES 130 (3) S82  1347-8613 2016/03 [Refereed]
  • Matsuoka Junki; Ozaki Tomoka; Tsubota Maho; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES 130 (3) S200  1347-8613 2016/03 [Refereed]
  • Tsubota Maho; Yamasoba Daichi; Domoto Risa; Sekiguchi Fumiko; Nishibori Masahiro; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 130 (3) S235 - S235 1347-8613 2016/03 [Refereed]
  • Maeda Mariko; Irie Yuhei; Tsubota Maho; Kubo Lisa; Sekiguchi Fumiko; Ishikura Hiroyasu; Nishibori Masahiro; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES 130 (3) S144  1347-8613 2016/03 [Refereed]
  • Kenji Mitani; Fumiko Sekiguchi; Takashi Maeda; Yukari Tanaka; Shigeru Yoshida; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 130 (3) 177 - 180 1347-8613 2016/03 [Refereed]
     
    We investigated mechanisms for the neuritogenesis caused by prostaglandin E-2 (PGE(2)) or intracellular cyclic AMP (cAMP) in sensory neuron-like ND7/23 cells. PGE(2) caused neuritogenesis, an effect abolished by an EP4 receptor antagonist or inhibitors of adenylyl cyclase (AC) or protein kinase A (PKA) and mimicked by the AC activator forskolin, dibutyryl cAMP (db-cAMP), and selective activators of PKA or Epac. ND7/23 cells expressed both Ca(v)3.1 and Ca(v)3.2 T-type Ca2+ channels (T-channels). The neuritogenesis induced by db-cAMP or PGE(2) was abolished by T-channel blockers. T-channels were functionally upregulated by db-cAMP. The PGE(2)/EP4/cAMP/T-channel pathway thus appears to mediate neuritogenesis in sensory neurons. (C) 2016 Japanese Pharmacological Society. Production and hosting by Elsevier B.V.
  • Daichi Yamasoba; Maho Tsubota; Risa Domoto; Fumiko Sekiguchi; Hiroyuki Nishikawa; Keyue Liu; Masahiro Nishibori; Hiroyasu Ishikura; Tetsushi Yamamoto; Atsushi Taga; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 130 (2) 139 - 142 1347-8613 2016/02 [Refereed]
     
    Nuclear HMGB1 that contains 3 cysteine residues is acetylated and secreted to the extracellular space, promoting inflammation via multiple molecules such as RAGE and TLR4. We thus evaluated and characterized the redox state-dependent effects of peripheral HMGB1 on nociception. Intraplantar (i.pl.) administration of bovine thymus-derived HMGB1 (bt-HMGB1), all-thiol HMGB1 (at-HMGB1) or disulfide HMGB1 (ds-HMGB1) caused long-lasting mechanical hyperalgesia in mice. The hyperalgesia following i.pl. bt-HMGB1 or at-HMGB1 was attenuated by RAGE inhibitors, while the ds-HMGB1-induced hyperalgesia was abolished by a TLR4 antagonist. Thus, nociceptive processing by peripheral HMGB1 is considered dependent on its redox states. (C) 2016 Japanese Pharmacological Society. Production and hosting by Elsevier B.V.
  • Yuka Aoki; Maho Tsubota; Yuta Nishimoto; Yumi Maeda; Fumiko Sekiguchi; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 130 (1) 38 - 41 1347-8613 2016/01 [Refereed]
     
    We examined the effects of intraplantar (i.pl.) administration of NaHS, an H2S donor, known to cause T-type Ca2+ channel (T-channel)-dependent mechanical hyperalgesia, on responsiveness to electric stimulation with 5, 250 and 2000 Hz sine waves (SW) that selectively excites C, A delta and A beta fibers, respectively. NaHS, given i.pl., caused behavioral hypersensitivity to SW stimulation at 5 Hz, but not 250 or 2000 Hz, in rats. NaHS also enhanced phosphorylation of spinal ERK following 5 Hz SW stimulation. Three distinct T-channel blockers abolished the NaHS-induced behavioral hypersensitivity to 5 Hz SW stimulation. Thus, H2S selectively sensitizes C-fiber nociceptors via T-channels. (C) 2016 Japanese Pharmacological Society. Production and hosting by Elsevier B.V.
  • Noriaki Nagai; Chiaki Yoshioka; Yoshimasa Ito; Yoshinori Funakami; Hiroyuki Nishikawa; Atsufumi Kawabata
    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES MDPI AG 16 (12) 29329 - 29344 1422-0067 2015/12 [Refereed]
     
    It was reported that cilostazol (CLZ) suppressed disruption of the microvasculature in ischemic areas. In this study, we have designed novel injection formulations containing CLZ nanoparticles using 0.5% methylcellulose, 0.2% docusate sodium salt, and mill methods (CLZ(nano) dispersion; particle size 81 +/- 59 nm, mean +/- S.D.), and investigated their toxicity and usefulness in a cerebral ischemia/reperfusion-induced injury model (MCAO/reperfusion mice). The pharmacokinetics of injections of CLZ(nano) dispersions is similar to that of CLZ solutions prepared with 2-hydroxypropyl--cyclodextrin, and no changes in the rate of hemolysis of rabbit red blood cells, a model of cell injury, were observed with CLZ(nano) dispersions. In addition, the intravenous injection of 0.6 mg/kg CLZ(nano) dispersions does not affect the blood pressure and blood flow, and the 0.6 mg/kg CLZ(nano) dispersions ameliorate neurological deficits and ischemic stroke in MCAO/reperfusion mice. It is possible that the CLZ(nano) dispersions will provide effective therapy for ischemic stroke patients, and that injection preparations of lipophilic drugs containing drug nanoparticles expand their therapeutic usage.
  • Kazuki Fukami; Fumiko Sekiguchi; Miku Yasukawa; Erina Asano; Ryuji Kasamatsu; Mai Ueda; Shigeru Yoshida; Atsufumi Kawabata
    BIOCHEMICAL PHARMACOLOGY PERGAMON-ELSEVIER SCIENCE LTD 97 (3) 300 - 309 0006-2952 2015/10 [Refereed]
     
    Neuroendocrine-differentiated prostate cancer cells may contribute to androgen-independent proliferation of surrounding cells through Ca2+-dependent secretion of mitogenic factors. Human prostate cancer LNCaP cells, when neuroendocrine-differentiated, overexpress Ca(v)3.2 T-type Ca2+ channels that contribute to Ca2+-dependent secretion. Given evidence for the acceleration of Ca(v)3.2 activity by hydrogen sulfide (H2S), we examined the roles of the H2S/Ca(v)3.2 pathway and then analyzed the molecular mechanisms of the Ca(v)3.2 overexpression in neuroendocrine-differentiated LNCaP cells. LNCaP cells were differentiated by dibutyryl cyclic AMP. Protein levels and T-type Ca2+ channeldependent currents (T-currents) were measured by immunoblotting and whole-cell pacth-clamp technique, respectively. Spontaneous release of prostatic acid phosphatase (PAP) was monitored to evaluate secretory function. The differentiated LNCaP cells exhibited neurite outgrowth, androgenindependent proliferation and upregulation of mitogenic factors, and also showed elevation of Ca(v)3.2 expression or T-currents. Expression of cystathionine-gamma-Iyase (CSE) and cystathionine-beta-synthase (CBS), H2S-forming enzymes, and spontaneous secretion of PAP increased following the differentiation. The augmented T-currents were enhanced by H2S donors and suppressed by inhibitors of CSE, but not CBS. The PAP secretion was reduced by inhibition of CSE or T-type Ca2+ channels. During differentiation, Egr-1 and REST, positive and negative transcriptional regulators for Ca(v)3.2, were upregulated and downregulated, respectively, and Egr-1 knockdown prevented the Ca(v)3.2 overexpression. Our data suggest that, in neuroendocrine-differentiated LNCaP cells, H2S formed by the upregulated CSE promotes the activity of the upregulated Ca(v)3.2, leading to the elevated secretory functions. The overexpression of Ca(v)3.2 appears to involve upregulation of Egr-1 and downregulation of REST. (C) 2015 Elsevier Inc. All rights reserved.
  • 原田 成信; 伊藤 由香里; 高嶋 一平; 王子田 彰夫; 川畑 篤史
    Otology Japan (一社)日本耳科学会 25 (4) 619 - 619 0917-2025 2015/09
  • Tsubota Maho; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 128 (3) S40 - S40 1347-8613 2015/07 [Refereed]
  • Hiruma Saki; Murakami; Nakayama) Masahiro; Tsubota Maho; Sekiguchi Fumiko; Matsuyama Kenji; Kimura Takeshi; Moriyama Masahiro; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES 128 (3) S110  1347-8613 2015/07 [Refereed]
  • Yamasoba Daichi; Seki Yukari; Yamanishi Hiroki; Tsubota Maho; Sekiguchi Fumiko; Yagi Hideki; Masuko Takashi; Nishibori Masahiro; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 128 (3) S104 - S104 1347-8613 2015/07 [Refereed]
  • Kazuki Fukami; Atsufumi Kawabata
    NITRIC OXIDE-BIOLOGY AND CHEMISTRY ACADEMIC PRESS INC ELSEVIER SCIENCE 46 50 - 54 1089-8603 2015/04 [Refereed]
     
    Hydrogen sulfide (H2S) is considered the third gasotransmitter following nitric oxide (NO) and carbon monoxide (CO) in the mammalian body including the brain, heart, blood vessels, liver, kidney, pancreas, lung, gastrointestinal tract and reproductive organs. H2S is formed endogenously from L-cysteine by multiple enzymes, such as cystathionine-gamma-lyase, cystathionine-beta-synthase and 3-mercaptopyruvate sulfurtransferase in combination with cysteine aminotransferase, and participates in a variety of biological events through a number of target molecules. Exogenous and/or endogenous H2S enhances the activity of T-type Ca2+. channels in NG108-15 cells and isolated dorsal root ganglion neurons that abundantly express Ca(v)3.2, and in Ca(v)3.2-transfected HEK293 cells. Ca(v)3.2 mediates not only the H2S-induced enhancement of pain signals in nociceptor neurons, but also neuronal differentiation characterized by neuritogenesis and functional upregulation of high voltage-activated Ca2+. channels in NG108-15 cells. In this review, we focus on the functional modulation by H2S of primarily Ca(v)3.2 T-type Ca2+ channels and the molecular mechanisms underlying the H2S-induced neuronal differentiation. (C) 2015 Elsevier Inc. All rights reserved.
  • 臨床を反映した動物モデルを用いた病態解明の最前線 急性膵炎・膵臓痛動物モデルを用いた病態解析 T型Ca2+チャネルおよびTRPチャネルの役割
    寺田 侑加; 坪田 真帆; 関口 富美子; 和田 恭一; 桑原 健; 高田 充隆; 川畑 篤史
    日本薬学会年会要旨集 (公社)日本薬学会 135年会 (1) 333 - 333 0918-9823 2015/03
  • Yuma Maeda; Fumiko Sekiguchi; Rumi Yamanaka; Ryo Sugimoto; Daichi Yamasoba; Shiori Tomita; Hiroyuki Nishikawa; Atsufumi Kawabata
    BIOLOGICAL CHEMISTRY WALTER DE GRUYTER GMBH 396 (2) 153 - 162 1431-6730 2015/02 [Refereed]
     
    We analyzed signaling mechanisms for prostaglandin E-2 (PGE(2)) production following activation of proteinase-activated receptor-1 (PAR1), a thrombin receptor, in preosteoblastic MC3T3-E1 cells. PAR1 stimulation caused PGE(2) release, an effect suppressed by inhibitors ;of COX-1, COX-2, iPLA(2), cPLA(2), MAP kinases (MAPKs), Src, EGF receptor (EGFR) tyrosine kinase (EGFR-TK) and matrix metalloproteinase (MMP), but not by an intracellular Ca2+ chelator or inhibitors of PI3 kinase, protein kinase C (PKC) and NF-kappa B. PAR1 activation induced phosphorylation of MAPKs and upregulation of COX-2. The phosphorylation of p38 MAPK was suppressed by inhibitors of Src and EGFR-TK. The COX-2 upregulation was dependent on ERK, p38, EGFR-TK, Src, and COX-2 itself. PAR1 activation also induced MEK-dependent phosphorylation of cAMP response element binding protein (CREB). All inhibitors of EP1, EP2, EP3 and EP4 receptors suppressed the PAR1-triggered PGE(2) release. Exogenously applied PGE(2) facilitated PAR1-triggered COX-2 upregulation, but it alone had no effect. Together, the PAR1-mediated PGE(2) production in MC3T3-E1 cells appears to involve iPLA(2) and cPLA(2) for arachidonic acid release, and the MEK/ERK/CREB and Src/MMP/EGFR/p38 pathways for COX-2 upregulation, which is facilitated by endogenous PGE(2) formed by COX-2. These signaling mechanisms might underlie the role of the thrombin/PAR1/PGE(2) system in the early stage of the bone healing.
  • Yuka Terada; Mayuko Fujimura; Sachiyo Nishimura; Maho Tsubota; Fumiko Sekiguchi; Atsufumi Kawabata
    JOURNAL OF NEUROSCIENCE RESEARCH WILEY-BLACKWELL 93 (2) 361 - 369 0360-4012 2015/02 [Refereed]
     
    Hydrogen sulfide (H2S), formed by multiple enzymes, including cystathionine--lyase (CSE), targets Ca(v)3.2 T-type Ca2+ channels (T channels) and transient receptor potential ankyrin-1 (TRPA1), facilitating somatic pain. Pancreatitis-related pain also appears to involve activation of T channels by H2S formed by the upregulated CSE. Therefore, this study investigates the roles of the Ca(v)3.2 isoform and/or TRPA1 in pancreatic nociception in the absence and presence of pancreatitis. In anesthetized mice, AP18, a TRPA1 inhibitor, abolished the Fos expression in the spinal dorsal horn caused by injection of a TRPA1 agonist into the pancreatic duct. As did mibefradil, a T-channel inhibitor, in our previous report, AP18 prevented the Fos expression following ductal NaHS, an H2S donor. In the mice with cerulein-induced acute pancreatitis, the referred hyperalgesia was suppressed by NNC 55-0396 (NNC), a selective T-channel inhibitor; zinc chloride; or ascorbic acid, known to inhibit Ca(v)3.2 selectively among three T-channel isoforms; and knockdown of Ca(v)3.2. In contrast, AP18 and knockdown of TRPA1 had no significant effect on the cerulein-induced referred hyperalgesia, although they significantly potentiated the antihyperalgesic effect of NNC at a subeffective dose. TRPA1 but not Ca(v)3.2 in the dorsal root ganglia was downregulated at a protein level in mice with cerulein-induced pancreatitis. The data indicate that TRPA1 and Ca(v)3.2 mediate the exogenous H2S-induced pancreatic nociception in naive mice and suggest that, in the mice with pancreatitis, Ca(v)3.2 targeted by H2S primarily participates in the pancreatic pain, whereas TRPA1 is downregulated and plays a secondary role in pancreatic nociceptive signaling. (c) 2014 Wiley Periodicals, Inc.
  • Masahiro Murakami-Nakayama; Maho Tsubota; Saki Hiruma; Fumiko Sekiguchi; Kenji Matsuyama; Takeshi Kimura; Masahiro Moriyama; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 127 (2) 223 - 228 1347-8613 2015/02 [Refereed]
     
    Ca(v)3.2 T-type Ca2+ channels targeted by H2S, a gasotransmitter, participate in cyclophosphamide-induced cystitis and bladder pain. Given that zinc selectively inhibits Ca(v)3.2 among T-channel isoforms and also exhibits antioxidant activity, we examined whether polaprezinc (zinc-L-carnosine), a medicine for peptic ulcer treatment and zinc supplementation, reveals preventive or therapeutic effects on bladder inflammation and/or pain in the mouse with cyclophosphamide-induced cystitis, a model for interstitial cystitis. Systemic administration of cyclophosphamide caused cystitis-related symptoms including increased bladder weight and vascular permeability, and histological signs of bladder edema, accompanied by bladder pain-like nociceptive behavior/referred hyperalgesia. All these symptoms were significantly attenuated by oral preadministration of polaprezinc at 400 mg/kg. The same dose of polaprezinc also prevented the increased malondialdehyde level, an indicator of lipid peroxidation, and protein upregulation of cystathionine-gamma-Iyase. an H2S-generating enzyme, but not occludin, a tight junction-related membrane protein, in the bladder tissue of cyclophosphamide-treated mice. Oral posttreatment with polaprezinc at 30-100 mg/kg reversed the nociceptive behavior/referred hyperalgesia in a dose-dependent manner without affecting the increased bladder weight. Together, our data show that zinc supplementation with polaprezinc prevents the cyclophosphamide-induced cystitis probably through the antioxidant activity, and, like T-channel blockers, reverses the established cystitis-related bladder pain in mice, suggesting novel therapeutic usefulness of polaprezinc. (C) 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.
  • Masayuki Takechi; Tetsuyuki Wada; Hideki Yagi; Takashi Masuko; Atsufumi Kawabata
    JOURNAL OF PHARMACY AND PHARMACOLOGY WILEY-BLACKWELL 67 (1) 126 - 132 0022-3573 2015/01 [Refereed]
     
    Objectives We tested if modulation of cytosolic K+ levels by ouabain, an inhibitor of Na+/K+-ATPase, exerts cytoprotection against distinct stressful stimuli in human leukemic cells. Methods The cytosolic K+, Na+ or Ca2+ levels and the cytotoxicity were evaluated by flow cytometry. Key findings Various cytotoxic chemicals and ultraviolet irradiation induced cell death and increased intracellular concentrations of K+, Na+ or Ca2+. Ouabain reduced the cytotoxicity and the elevation of cytosolic levels of K+ but not those of Na+ or Ca2+. Conclusions Our data thus suggest that elevated cytosolic K+ levels are associated with the cytotoxicity in response to distinct stressful stimuli and that ouabain exerts cytoprotection most probably by regulating intracellular K+ levels.
  • Yuka Terada; Atsufumi Kawabata
    Handbook of Experimental Pharmacology Springer New York LLC 230 217 - 230 1865-0325 2015 [Refereed]
     
    Hydrogen sulfide (H2S) formed by multiple enzymes including cystathionine- γ-lyase (CSE) targets Cav3.2 T-type Ca2+ channels (T-channels) and transient receptor potential ankyrin-1 (TRPA1). Intraplantar and intracolonic administration of H2S donors promotes somatic and visceral pain, respectively, via activation of Cav3.2 and TRPA1 in rats and/or mice. Injection of H2S donors into the plantar tissues, pancreatic duct, colonic lumen, or bladder causes T-channeldependent excitation of nociceptors, determined as phosphorylation of ERK or expression of Fos in the spinal dorsal horn. Electrophysiological studies demonstrate that exogenous and/or endogenous H2S facilitates membrane currents through T-channels in NG108-15 cells and isolated mouse dorsal root ganglion (DRG) neurons that abundantly express Cav3.2 and also in Cav3.2-transfected HEK293 cells. In mice with cerulein-induced pancreatitis and cyclophosphamide-induced cystitis, visceral pain and/or referred hyperalgesia are inhibited by CSE inhibitors and by pharmacological blockade or genetic silencing of Cav3.2, and CSE protein is upregulated in the pancreas and bladder. In rats with neuropathy induced by L5 spinal nerve cutting or by repeated administration of paclitaxel, an anticancer drug, the neuropathic hyperalgesia is reversed by inhibitors of CSE or T-channels and by silencing of Cav3.2. Upregulation of Cav3.2 protein in DRG is detectable in the former, but not in the latter, neuropathic pain models. Thus, H2S appears to function as a nociceptive messenger by facilitating functions of Cav3.2 and TRPA1, and the enhanced function of the CSE/H2S/Cav3.2 pathway is considered to be involved in the pancreatitis- and cystitis-related pain and in neuropathic pain.
  • Maho Tsubota; Atsufumi Kawabata
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 134 (12) 1245 - 1252 0031-6903 2014/12 [Refereed]
     
    Hydrogen sulfide (H2S), the third known gaseous transmitter following nitric oxide and carbon monoxide, is generated by multiple enzymes including cystathionine-gamma-lyase (CSE) in vivo. We previously demonstrated that H2S activates Ca(v)3.2 T-type Ca2+ channels expressed on sensory neurons, leading to hyperalgesia and facilitation of inflammation. Here, we describe the role of H2S in processing of colonic pain and inflammation. Intracolonic (i.col.) administration of NaHS, an H2S donor, to mice evoked colonic pain-like nociceptive behavior and referred hyperalgesia accompanied by phosphorylation of ERK in the superficial layers of spinal dorsal horn, a marker for excitation of nociceptive neurons. The pronociceptive effect of NaHS was abolished by inhibitors or knockdown of Ca(v)3.2 and by an inhibitor of TRPA1, another target molecule of H2S. In rats with colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS), on the other hand, repeated i.col. administration of NaHS prevented colonic ulcer and inflammatory symptoms, which were inhibited by ablation of capsaicin-sensitive sensory neurons or T-type Ca2+ channel inhibitor. NaHS, given i.col., caused phosphorylation of ERK in the spinal dorsal horn of rats with TNBS-induced colitis, but not of naive rats. In TNBS-treated rats, Ca(v)3.2 was upregulated in the dorsal root ganglia, while CSE was downregulated in the colon. Taken together, these findings suggest that inhibitors of the CSE/H2S/Ca(v)3.2 or TRPA1 pathways might be useful for the treatment of colonic pain diseases such as irritable bowel syndrome, while H2S donors or Ca(v)3.2 activators might be useful for the treatment of inflammatory bowel disease including Crohn's disease.
  • Junichi Tanaka; Kaoru Yamaguchi; Hiroyasu Ishikura; Maho Tsubota; Fumiko Sekiguchi; Yukari Seki; Toshifumi Tsujiuchi; Akira Murai; Takehiro Umemura; Atsufumi Kawabata
    NEUROPHARMACOLOGY PERGAMON-ELSEVIER SCIENCE LTD 79 112 - 118 0028-3908 2014/04 [Refereed]
     
    High mobility group box 1 (HMGB1), one of damage-associated molecular patterns (DAMPs), plays roles in not only inflammation but also processing of somatic pain. Given that no evidence for roles of HMGB1 in visceral pain signaling is available, we asked if HMGB1 participates in bladder pain accompanying cystitis caused by cyclophosphamide in mice, using the anti-HMGB1 neutralizing antibody and recombinant human soluble thrombomodulin (rhsTM) that sequesters HMGB1 and promotes its degradation by thrombin. Cyclophosphamide, administered i.p., caused bladder pain-like nociceptive behavior and referred hyperalgesia accompanying cystitis symptoms including increased bladder weight, an indicator of edema, in mice. The cyclophosphamide-induced bladder pain and referred hyperalgesia, but not increased bladder weight, were prevented by i.p. preadministration of the anti-HMGB1 neutralizing antibody or rhsTM. HMGB1, given i.p., facilitated the bladder pain and referred hyperalgesia caused by a subeffective dose of cyclophosphamide, an effect blocked by rhsTM. In the cyclophosphamide-treated mice, HMGB1 levels greatly decreased in the bladder tissue, particularly in the urothelial cells, but did not change in the plasma. Low molecular weight heparin, known to inhibit the receptor for advanced glycation end products (RAGE), but not lipopolysaccharide from Rhodobacter sphaeroides, an inhibitor of toll-like receptor 4 (TLR4), blocked the cyclophosphamide-induced bladder pain and referred hyperalgesia. Thus, our data indicate involvement of HMGB1 in the cyclophosphamide-induced bladder pain signaling, but not cystitis itself, and suggest that targeting HMGB1 with rhsTM or blocking RAGE might serve as a novel therapeutic strategy for the management of bladder pain. (C) 2013 Elsevier Ltd. All rights reserved.
  • Fumiko Sekiguchi; Yosuke Miyamoto; Daiki Kanaoka; Hiroki Ide; Shigeru Yoshida; Tsuyako Ohkubo; Atsufumi Kawabata
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ACADEMIC PRESS INC ELSEVIER SCIENCE 445 (1) 225 - 229 0006-291X 2014/02 [Refereed]
     
    Hydrogen sulfide (H2S), a gasotransmitter, is formed from L-cysteine by multiple enzymes including cystathionine-gamma-lyase (CSE). We have shown that an H2S donor, NaHS, causes hyperalgesia in rodents, an effect inhibited by knockdown of Ca(v)3.2 T-type Ca2+ channels (T-channels), and that NaHS facilitates T-channel-dependent currents (T-currents) in NG108-15 cells that naturally express Ca(v)3.2. In the present study, we asked if endogenous and exogenous H2S participates in regulation of the channel functions in Ca(v)3.2-transfected HEK293 (Ca(v)3.2-HEK293) cells. DL-Propargylglycine (PPG), a CSE inhibitor, significantly decreased T-currents in Ca(v)3.2-HEK293 cells, but not in NG108-15 cells. NaHS at 1.5 mM did not affect T-currents in Ca(v)3.2-HEK293 cells, but enhanced T-currents in NG108-15 cells. In the presence of PPG, NaHS at 1.5 mM, but not 0.1-0.3 mM, increased T-currents in Ca(v)3.2-HEK293 cells. Similarly, Na2S, another H2S donor, at 0.1-0.3 mM significantly increased T-currents in the presence, but not absence, of PPG in Ca(v)3.2-HEK293 cells. Expression of CSE was detected at protein and mRNA levels in HEK293 cells. Intraplantar administration of Na2S, like NaHS, caused mechanical hyperalgesia, an effect blocked by NNC 55-0396, a T-channel inhibitor. The in vivo potency of Na2S was higher than NaHS. These results suggest that the function of Ca(v)3.2 T-channels is tonically enhanced by endogenous H2S synthesized by CSE in Ca(v)3.2-HEK293 cells, and that exogenous H2S is capable of enhancing Ca(v)3.2 function when endogenous H2S production by CSE is inhibited. In addition, Na2S is considered a more potent H2S donor than NaHS in vitro as well as in vivo. (C) 2014 Elsevier Inc. All rights reserved.
  • 苦参由来T型Ca2+チャネル阻害物質の検索 ヒトCav3.2発現HEK293細胞における電気生理学的検討とマウスにおける硫化水素誘起痛覚過敏に対する抑制効果の評価
    藤田 友代; 関口 富美子; 出口 貴浩; 吉田 繁; 村田 和也; 松田 秀秋; 大久保 つや子; 川畑 篤史
    日本薬理学雑誌 (公社)日本薬理学会 142 (5) 10P - 10P 0015-5691 2013/11
  • Nakayama M; Fujiwara M; Nakamura T; Azuma T; Matzno S; Kamikonya N; Kimura T; Matsuyama K; Kawabata A
    Jpn. J. Drug Inform. (一社)日本医薬品情報学会 15 (3) 133 - 138 1345-1464 2013/11 [Refereed]
     
    胃潰瘍の含亜鉛治療薬であるポラプレジンク(PZ)を水溶性のカルボキシビニルポリマー(CP)存在下で懸濁液として調製してその安定性について検討し、口腔粘膜炎の治療薬としての有効性を評価した。安定性試験では調製後28時間にわたり、そのpH、粘度、接着性およびPZ含量に変化は見られなかった。口腔粘膜炎の重症度分類に基づいた臨床評価では、PZ使用者(PZ群)の口腔粘膜炎の重症度が対照としたPZ非使用者(対照群)のそれに比べて、6週時(p=0.016)と7週時(p=0.018)のいずれでも有意に低かった。また、グレード3の重度口腔粘膜炎のPZ群と対照群における発生率は、6週時でそれぞれ15.0%と41.7%、7週時ではそれぞれ15.0%と33.3%であった。以上より、PZ-CPうがい薬は化学放射線療法で誘導される口腔粘膜炎の増悪を阻止し、その治癒を促進すると思われた。
  • Junichi Tanaka; Yukari Seki; Hiroyasu Ishikura; Maho Tsubota; Fumiko Sekiguchi; Kaoru Yamaguchi; Akira Murai; Takehiro Umemura; Atsufumi Kawabata
    British Journal of Pharmacology 170 (6) 1233 - 1241 0007-1188 2013/11 [Refereed]
     
    Background and Purpose High-mobility group box 1 (HMGB1), a nuclear protein, is actively or passively released during inflammation. Recombinant human soluble thrombomodulin (rhsTM), a medicine for treatment of disseminated intravascular coagulation (DIC), sequesters HMGB1 and promotes its degradation. Given evidence for involvement of HMGB1 in pain signalling, we determined if peripheral HMGB1 causes hyperalgesia, and then asked if rhsTM modulates the HMGB1-dependent hyperalgesia. Experimental Approach Mechanical nociceptive threshold and swelling in rat hindpaw were determined by the paw pressure test and by measuring paw thickness, respectively, and HMGB1 levels in rat hindpaw plantar tissue, dorsal root ganglion (DRG) and serum were determined by Western blotting or elisa. Key Results Intraplantar (i.pl.) administration of HMGB1 rapidly evoked paw swelling and gradually caused hyperalgesia in rats. Systemic administration of rhsTM abolished HMGB1-induced hyperalgesia, and partially blocked paw swelling. LPS, administered i.pl., rapidly produced mild paw swelling, and gradually caused hyperalgesia. The anti-HMGB1 neutralizing antibody abolished LPS-induced hyperalgesia, but partially inhibited paw swelling. rhsTM at a high dose, 10 mg kg-1, prevented both hyperalgesia and paw swelling caused by LPS. In contrast, rhsTM at low doses, 0.001-1 mg kg-1, abolished the LPS-induced hyperalgesia, but not paw swelling. HMGB1 levels greatly decreased in the hindpaw, but not DRG. Serum HMGB1 tended to increase after i.pl. LPS in rats pretreated with vehicle, but not rhsTM. Conclusion and Implications These data suggest that peripheral HMGB1 causes hyperalgesia, and that rhsTM abolishes HMGB1-dependent hyperalgesia, providing novel evidence for therapeutic usefulness of rhsTM as an analgesic. © 2013 The British Pharmacological Society.
  • Yuka Terada; Mayuko Fujimura; Sachiyo Nishimura; Maho Tsubota; Fumiko Sekiguchi; Hiroyuki Nishikawa; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 123 (3) 284 - 287 1347-8613 2013/11 [Refereed]
     
    We examined if TRPA1, like TRPV1, contributes to pancreatic nociceptor excitation following proteinase-activated receptor-2 (PAR2) stimulation and to pancreatitis-related pain in mice. A PAR2-activating peptide, infused into the pancreatic duct, caused spinal Fos expression, which was prevented by AP18, a TRPA1 inhibitor. Repeated administration of cerulein caused referred hyperalgesia accompanying pancreatitis, which was reversed by SB366791, a TRPV1 inhibitor, but not AP18. AP18, administered in combination with a subeffective dose of SB366791, significantly suppressed the referred hyperalgesia. Our findings suggest that TRPA1, like TRPV1, mediates PAR2-triggered pancreatic nociception and that TRPA1 in collaboration with TRPV1 latently contributes to pancreatitis-related pain.
  • Hiroyuki Nishikawa; Hitomi Hayashi; Satoko Kubo; Maho Tsubota-Matsunami; Fumiko Sekiguchi; Atsufumi Kawabata
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 36 (8) 1278 - 1282 0918-6158 2013/08 [Refereed]
     
    Hydrogen sulfide (H2S), a gasotransmitter, plays a variety of roles in the mammalian body including the cardiovascular system. Given evidence that H2S donors including NaHS inhibit human platelet aggregation, we examined and characterized the effects of NaFIS on rabbit platelet aggregation and cytosolic Ca2+ mobilization. Rabbit platelet aggregation was determined in platelet-rich plasma (PRP) and washed platelets. Intracellular Ca2+ levels were monitored in Fura2-loaded washed platelets. NaHS prevented rabbit platelet aggregation induced by collagen or ADP, and the effective concentration range of NaHS was 0.1-0.3 mM in PRP and 1-3 mM in washed platelets. In washed platelets, NaHS attenuated cytosolic Ca2+ mobilization induced by collagen or ADP and also reduced platelet aggregation induced by ionomycin, a Ca2+ ionophore. The antiplatelet effect of NaHS was blocked by an adenylyl cyclase inhibitor and enhanced by a phosphodiesterase inhibitor. H2S thus suppresses rabbit platelet aggregation by interfering with both upstream and downstream signals of cytosolic Ca2+ mobilization in a cAMP-dependent manner.
  • Fumiko Sekiguchi; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 122 (4) 244 - 250 1347-8613 2013/08 [Refereed]
     
    Low-voltage-activated T-type Ca2+ channels (T-channels), especially Ca(v)3.2 among the three isoforms (Ca(v)3.1, Ca(v)3.2, and Ca(v)3.3), are now considered to play pivotal roles in processing of pain signals. Ca(v)3.2 T-channels are functionally modulated by extracellular substances such as hydrogen sulfide and ascorbic acid, by intracellular signaling molecules including protein kinases, and by glycosylation. Ca(v)3.2 T-channels are abundantly expressed in both peripheral and central endings of the primary afferent neurons, regulating neuronal excitability and release of excitatory neurotransmitters such as substance P and glutamate, respectively. Functional upregulation of Ca(v)3.2 T-channels is involved in the pathophysiology of inflammatory, neuropathic, and visceral pain. Thus, Ca(v)3.2 T-channels are considered to serve as novel targets for development of drugs for treatment of intractable pain resistant to currently available analgesics.
  • Kawabata A
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica The Japanese Pharmacological Society 141 (2) 81 - 84 0015-5691 2013/02 [Refereed]
     
    がん化学療法の副作用として生じる神経障害性疼痛は，患者のQOL低下を招くだけでなく，化学療法の中止の原因にもなりうるので，その対策は急務である．神経障害性疼痛薬物療法の第一選択薬とされているプレガバリンは，高電位活性化型Ca2+チャネルのα2δサブユニットを標的とした薬物であるが，プレガバリンが作用しないT型（低電位活性化型）Ca2+チャネルのうちCav3.2が神経障害性疼痛の病態に関与することが明らかとなり，T型Ca2+チャネル阻害薬が神経障害性疼痛の治療に応用できる可能性が示唆されている．Cav3.2は，内因性気体メディエーターである硫化水素やL-システインによって直接活性化され，またプロスタグランジンE2によりプロテインキナーゼA依存的に活性化されるほか，生体内のZn2+やビタミンCによって機能が抑制される．本稿では，Cav3.2 T型Ca2+チャネルの分子機能調節機構を概説し，特にがん化学療法に伴う神経障害性疼痛の治療標的分子としての可能性について述べる．
  • Fumiko Sekiguchi; Yuka Aoki; Maiko Nakagawa; Daiki Kanaoka; Yuta Nishimoto; Maho Tsubota-Matsunami; Rumi Yamanaka; Shigeru Yoshida; Atsufumi Kawabata
    BRITISH JOURNAL OF PHARMACOLOGY WILEY-BLACKWELL 168 (3) 734 - 745 0007-1188 2013/02 [Refereed]
     
    Background and Purpose The Cav3.2 isoform of T-type Ca2+ channels (T channels) is sensitized by hydrogen sulfide, a pro-nociceptive gasotransmitter, and also by PKA that mediates PGE2-induced hyperalgesia. Here we examined and analysed Cav3.2 sensitization via the PGE2/cAMP pathway in NG108-15 cells that express Cav3.2 and produce cAMP in response to PGE2, and its impact on mechanical nociceptive processing in rats. Experimental Approach In NG108-15 cells and rat dorsal root ganglion (DRG) neurons, T-channel-dependent currents (T currents) were measured with the whole-cell patch-clamp technique. The molecular interaction of Cav3.2 with A-kinase anchoring protein 150 (AKAP150) and its phosphorylation were analysed by immunoprecipitation/immunoblotting in NG108-15 cells. Mechanical nociceptive threshold was determined by the paw pressure test in rats. Key Results In NG108-15 cells and/or rat DRG neurons, dibutyryl cAMP (db-cAMP) or PGE2 increased T currents, an effect blocked by AKAP St-Ht31 inhibitor peptide (AKAPI) or KT5720, a PKA inhibitor. The effect of PGE2 was abolished by RQ-00015986-00, an EP4 receptor antagonist. AKAP150 was co-immunoprecipitated with Cav3.2, regardless of stimulation with db-cAMP, and Cav3.2 was phosphorylated by db-cAMP or PGE2. In rats, intraplantar (i.pl.) administration of db-cAMP or PGE2 caused mechanical hyperalgesia, an effect suppressed by AKAPI, two distinct T-channel blockers, NNC 55-0396 and ethosuximide, or ZnCl2, known to inhibit Cav3.2 among T channels. Oral administration of RQ-00015986-00 suppressed the PGE2-induced mechanical hyperalgesia. Conclusion and Implications Our findings suggest that PGE2 causes AKAP-dependent phosphorylation and sensitization of Cav3.2 through the EP4 receptor/cAMP/PKA pathway, leading to mechanical hyperalgesia in rats.
  • Tomoko Takahashi; Kazumasa Okubo; Shota Kojima; Hiroyuki Nishikawa; Motohide Takemura; Maho Tsubota-Matsunami; Fumiko Sekiguchi; Atsufumi Kawabata
    Journal of Pharmacological Sciences 122 (1) 51 - 54 1347-8613 2013 [Refereed]
     
    We evaluated the effect of buprenorphine, a mixed agonist for μ-opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors, in neuropathic rats, using the paw pressure test. Buprenorphine, administered i.p. at 50, but not 20, μg/kg, exhibited naloxone-reversible analgesic activity in naïve rats. In contrast, buprenorphine at 0.5-20 μg/kg produced a naloxone-sensitive antihyperalgesic effect in the L5 spinal nerve-injured neuropathic rats. Intrathecal injection of [N-Phe1]nociceptin(1-13) NH2, a NOP-receptor antagonist, reversed the effect of buprenorphine in neuropathic rats, but not in naïve rats. Together, buprenorphine suppresses neuropathic hyperalgesia by activating NOP and opioid receptors, suggesting its therapeutic usefulness in treatment of neuropathic pain. © The Japanese Pharmacological Society.
  • F. Sekiguchi; Y. Matsumoto; Y. Maeda; M. Tsubota-Matsunami; H. Nishikawa; A. Kawabata
    JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY POLISH PHYSIOLOGICAL SOC 63 (6) 571 - 576 0867-5910 2012/12 [Refereed]
     
    To clarify the relationship between Helicobacter pylori (H. pylori), a risk factor for gastritis, peptic ulcer and gastric cancer, and proteinase-activated receptors (PARs) that contribute to inflammatory responses, we determined and characterized the biological activity of H. pylori components in the mammalian cells that express PARs. The activity of H. pylori extracts was assessed in distinct cell lines with high expression of PAR1 (RGM1 cells), PAR2 (A549 cells), or PAR2 and PAR4 (HCT-15 cells). A PAR1-activating peptide (AP), but not H. pylori extracts, caused prostaglandin E-2 (PGE(2)) release in RGM1 cells. On the other hand, H. pylori extracts produced release of PGE2 and interleukin-8 (IL-8) in A549 and HCT-15 cells, respectively, as a PAR2-AP did. The activity of H. pylori extracts in A549 cells was not affected by a proteinase inhibitor or exposure to boiling, but abolished by inhibitors of lipopolysaccharide (LPS), IRAK-1/4 or NF-kappa B. The activity of H. pylori extracts in HCT-15 cells was partially suppressed by boiling or the proteinase inhibitor. In rat platelets that express PAR4 and PAR3, like a PAR4-AP, H. pylori extracts induced aggregation when assessed in platelet rich plasma, an effect unaffected by the proteinase inhibitor, but did not cause aggregation of washed rat platelets that responded to the PAR4-AP or thrombin. The present study thus shows the biological activities of H. pylori extracts in A549 and HCT-15 cells or rat platelets, and suggests that they are not mediated by any PAR-activating proteinases, but may involve the other pathogenic factors including LPS.
  • TRPA1チャネルは硫化水素およびPAR2の下流シグナル分子として膵臓痛の情報伝達に寄与する
    寺田 侑加; 藤村 茉由子; 別府 幸容; 坪田 真帆; 川畑 篤史
    日本薬理学雑誌 (公社)日本薬理学会 140 (4) 3P - 3P 0015-5691 2012/10
  • Maho Matsunami; Takahiro Miki; Kanae Nishiura; Yuko Hayashi; Yasumasa Okawa; Hiroyuki Nishikawa; Fumiko Sekiguchi; Lisa Kubo; Tomoka Ozaki; Toshifumi Tsujiuchi; Atsufumi Kawabata
    BRITISH JOURNAL OF PHARMACOLOGY WILEY-BLACKWELL 167 (4) 917 - 928 0007-1188 2012/10 [Refereed]
     
    BACKGROUND AND PURPOSE Hydrogen sulfide (H2S), generated by enzymes such as cystathionine-?-lyase (CSE) from L-cysteine, facilitates pain signals by activating the Cav3.2 T-type Ca2+ channels. Here, we assessed the involvement of the CSE/H2S/Cav3.2 pathway in cystitis-related bladder pain. EXPERIMENTAL APPROACH Cystitis was induced by i.p. administration of cyclophosphamide in mice. Bladder pain-like nociceptive behaviour was observed and referred hyperalgesia was evaluated using von Frey filaments. Phosphorylation of ERK in the spinal dorsal horn was determined immunohistochemically following intravesical administration of NaHS, an H2S donor. KEY RESULTS Cyclophosphamide caused cystitis-related symptoms including increased bladder weight, accompanied by nociceptive changes (bladder pain-like nociceptive behaviour and referred hyperalgesia). Pretreatment with DL-propargylglycine, an inhibitor of CSE, abolished the nociceptive changes and partly prevented the increased bladder weight. CSE protein in the bladder was markedly up-regulated during development of cystitis. Mibefradil or NNC 550396, blockers of T-type Ca2+ channels, administered after the symptoms of cystitis appeared, reversed the nociceptive changes. Further, silencing of Cav3.2 protein by repeated intrathecal administration of mouse Cav3.2-targeting antisense oligodeoxynucleotides also significantly attenuated the nociceptive changes, but not the increased bladder weight. Finally, the number of cells staining positive for phospho-ERK was increased in the superficial layer of the L6 spinal cord after intravesical administration of NaHS, an effect inhibited by NNC 550396. CONCLUSION AND IMPLICATIONS Endogenous H2S, generated by up-regulated CSE, caused bladder pain and referred hyperalgesia through the activation of Cav3.2 channels, one of the T-type Ca2+ channels, in mice with cyclophosphamide-induced cystitis.
  • Kazumasa Okubo; Midori Matsumura; Yudai Kawaishi; Yuka Aoki; Maho Matsunami; Yasumasa Okawa; Fumiko Sekiguchi; Atsufumi Kawabata
    BRITISH JOURNAL OF PHARMACOLOGY WILEY-BLACKWELL 166 (5) 1738 - 1743 0007-1188 2012/07 [Refereed]
     
    BACKGROUND AND PURPOSE Hydrogen sulfide, a gasotransmitter, facilitates somatic pain signals via activation of Cav3.2 T-type calcium channels in rats. Given evidence for the activation of transient receptor potential ankyrin-1 (TRPA1) channels by H2S, we asked whether TRPA1 channels, in addition to Cav3.2 channels, contribute to the H2S-induced mechanical hyperalgesia and allodynia in mice. EXPERIMENTAL APPROACH Mechanical hyperalgesia and allodynia were evaluated by the von Frey test in mice. Cav3.2 or TRPA1 channels in the sensory neurons were silenced by repeated intrathecal administration of antisense oligodeoxynucleotides in mice. KEY RESULTS Intraplantar administration of NaHS evoked hyperalgesia and allodynia in mice, an effect attenuated or abolished by NNC 550396 or mibefradil, T-type calcium channel blockers, and by ascorbic acid or zinc chloride, known to selectively inhibit Cav3.2 channels, out of the three isoforms of T-type calcium channels. Silencing of Cav3.2 channels in the sensory neurons also prevented the NaHS-induced hyperalgesia and allodynia in mice. The NaHS-induced hyperalgesia and allodynia in mice were significantly suppressed by AP18, a TRPA1 channel blocker, and by silencing of TRPA1 channels in the sensory neurons. CONCLUSIONS AND IMPLICATIONS Mechanical hyperalgesia and allodynia induced by NaHS/H2S required activation of both Cav3.2 and TRPA1 channels in mice.
  • Maho Tsubota-Matsunami; Yumi Noguchi; Yasumasa Okawa; Fumiko Sekiguchi; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 119 (3) 293 - 296 1347-8613 2012/07 [Refereed]
     
    Luminal hydrogen sulfide (H2S), a gasotransmitter, causes colonic pain / referred hyperalgesia in mice, most probably via activation of T-type Ca2+ channels. Here we analyzed the mechanisms for H2S-induced facilitation of colonic pain signals. Intracolonic administration of NaHS, an H2S donor, evoked visceral pain-like nociceptive behavior and referred hyperalgesia in mice, an effect abolished by NNC 55-0396, a selective T-type Ca2+-channel blocker, or by knockdown of Ca(v)3.2. AP18, a TRPA1 blocker, also prevented the NaHS-induced colonic pain and referred hyperalgesia. These findings demonstrate that H2S-induced colonic pain and referred hyperalgesia require activation of both Ca(v)3.2 and TRPA1 channels in mice.
  • Kazumasa Okubo; Hiroki Nakanishi; Maho Matsunami; Hiroharu Shibayama; Atsufumi Kawabata
    BRITISH JOURNAL OF PHARMACOLOGY WILEY-BLACKWELL 166 (3) 1058 - 1068 0007-1188 2012/06 [Refereed]
     
    BACKGROUND AND PURPOSE Cav3.2 T-type calcium channels, targeted by H2S, are involved in neuropathic hyperalgesia in rats and ascorbic acid inhibits Cav3.2 channels. Therefore, we evaluated the effects of intraplantar (i.pl.) administration of ascorbic acid or topical application of disodium isostearyl 2-O-L-ascorbyl phosphate (DI-VCP), a skin-permeable ascorbate derivative on hyperalgesia induced by NaHS, an H2S donor, and on neuropathic hyperalgesia. EXPERIMENTAL APPROACH In rats mechanical hyperalgesia was evoked by i.pl. NaHS, and neuropathic hyperalgesia was induced by L5 spinal nerve cutting (L5SNC) or by repeated administration of paclitaxel, an anti-cancer drug. Dermal ascorbic acid levels were determined colorimetrically. KEY RESULTS The NaHS-evoked Cav3.2 channel-dependent hyperalgesia was inhibited by co-administered ascorbic acid. Topical application of DI-VCP, but not ascorbic acid, prevented the NaHS-evoked hyperalgesia, and also increased dermal ascorbic acid levels. Neuropathic hyperalgesia induced by L5SNC or paclitaxel was reversed by i.pl. NNC 550396, a selective T-type calcium channel blocker, ascorbic acid or DI-VCP, and by topical DI-VCP, but not by topical ascorbic acid. The effects of i.pl. ascorbic acid and topical DI-VCP in the paclitaxel-treated rats were characterized by the faster onset and greater magnitude, compared with their effects in the L5SNC rats. Dermal ascorbic acid levels in the hindpaw significantly decreased after paclitaxel treatment, but not L5SNC, which was reversed by topical DI-VCP. CONCLUSIONS AND IMPLICATIONS Ascorbic acid, known to inhibit Cav3.2 channels, suppressed neuropathic hyperalgesia. DI-VCP ointment for topical application may be of benefit in the treatment of neuropathic pain.
  • M. Matsunami; S. Kirishi; T. Okui; A. Kawabata
    JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY POLISH PHYSIOLOGICAL SOC 63 (1) 61 - 68 0867-5910 2012/02 [Refereed]
     
    Hydrogen sulfide (H2S) is generated from L-cysteine by certain enzymes including cystathionine-gamma-lyase (CSE) and cystathionine-beta-synthase (CBS), and causes excitation of nociceptors mainly via activation of Ca(v)3.2 T-type Ca2+ channels in the peripheral tissue, facilitating somatic and colonic pain. Here, we investigated whether sensory nerves and Ca(v)3.2 are involved in the H2S-induced mucosal cytoprotection against 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. Colitis was evaluated 3 days after intracolonic (i.e.) TNBS in the rat. Phosphorylation of ER K in the spinal dorsal horn was detected by immunohistochemistry. Protein expression of Ca(v)3.2 in the dorsal root ganglia (DRG) and of CSE and CBS in the colon was determined by Western blotting. Repeated i.e. NaHS significantly suppressed the TNBS-induced colitis in rats, an effect prevented by ablation of sensory nerves with repeated administration of capsaicin. Repeated pretreatment with T-type Ca2+ channel blockers including ethosuximide significantly reduced the protective effects of repeated i.e. NaHS in the rats with TNBS-induced colitis. A single i.e. administration of NaHS induced ethosuximide-sensitive prompt phosphorylation of ERK in the spinal dorsal horn at T13 and L6-S1 levesl in the rats 1 day or 3 days after TNBS treatment, but not in naive rats. Ca(v)3.2 protein was upreuulated in DRG 1 day after i.e. TNBS in rats, while CSE, but not CBS, protein was downregulated in the colon. Our findings suggest that luminal H2S causes excitation of sensory nerves most probably by activating Ca(v)3.2 T-type Ca2+ channels that are upregulated in the early stage of colitis, leading to colonic mucosal cytoprotection in rats.
  • Atsufumi Kawabata; Maho Matsunami
    CELL/TISSUE INJURY AND CYTOPROTECTION/ORGANOPROTECTION IN THE GASTROINTESTINAL TRACT: MECHANISMS, PREVENTION AND TREATMENT KARGER 30 212 - 218 0302-0665 2012 [Refereed]
     
    Hydrogen sulfide (H2S), a gasotransmitter, is endogenously formed from L-cysteine by certain enzymes including cystathionine-gamma-lyase (CSE) in the mammalian body. H2S sensitizes Ca(v)3.2 T-type calcium channels, leading to excitation of sensory neurons followed by somatic hyperalgesia in rats and mice. The enhanced activity of the H2S/Ca(v)3.2 system is involved in the neuropathic pain/hyperalgesia induced by repeated administration of paclitaxel, an anti-cancer drug, or by spinal nerve injury. It is also noteworthy that the H2S-induced mechanical hyperalgesia requires activation of both Ca(v)3.2 and transient receptor potential A1 (TRPA1) channels in mice. H2S and Ca(v)3.2 T-type calcium channels are also involved in processing of visceral nociception including colonic, pancreatic and bladder pain. Endogenous H2S formed by upregulated CSE contributes to the pancreatitis-related pain. Further, the excitation of sensory nerves by H2S through T-type calcium channels exerts mucosal cytoprotection against colitis in rats. Together, endogenous H2S formed by CSE appears to stimulate sensory nerves by targeting Ca(v)3.2 1-type calcium channels and, in some cases, TRPA1 channels, leading to facilitation of somatic and visceral pain signals and also contributing to colonic mucosal cytoprotection. Thus, the CSE/H2S/Ca(v)3.2 system may serve as therapeutic targets for treatment of neuropathic or visceral pain and of colitis. Copyright (C) 2012 S. Karger AG, Basel
  • Yuko Kurokawa; Fumiko Sekiguchi; Satoko Kubo; Yoshiko Yamasaki; Sachi Matsuda; Yukari Okamoto; Teruki Sekimoto; Anna Fukatsu; Hiroyuki Nishikawa; Toshiaki Kume; Nobuyuki Fukushima; Akinori Akaike; Atsufumi Kawabata
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ACADEMIC PRESS INC ELSEVIER SCIENCE 414 (4) 727 - 732 0006-291X 2011/11 [Refereed]
     
    Hydrogen sulfide (H(2)S), a gasotransmitter, exerts both neurotoxicity and neuroprotection, and targets multiple molecules including NMDA receptors, T-type calcium channels and NO synthase (NOS) that might affect neuronal viability. Here, we determined and characterized effects of NaHS, an H(2)S donor, on cell viability in the primary cultures of mouse fetal cortical neurons. NaHS caused neuronal death, as assessed by LDH release and trypan blue staining, but did not significantly reduce the glutamate toxicity. The neurotoxicity of NaHS was resistant to inhibitors of NMDA receptors, T-type calcium channels and NOS, and was blocked by inhibitors of MEK, but not JNK, p38 MAP kinase, PKC and Src. NaHS caused prompt phosphorylation of ERK and upregulation of Bad, followed by translocation of Bax to mitochondria and release of mitochondrial cytochrome c(1) leading to the nuclear condensation/fragmentation. These effects of NaHS were suppressed by the MEK inhibitor. Our data suggest that the NMDA receptor-independent neurotoxicity of H(2)S involves activation of the MEK/ERK pathway and some apoptotic mechanisms. (C) 2011 Elsevier Inc. All rights reserved.
  • Atsufumi Kawabata
    Biological and Pharmaceutical Bulletin 34 (8) 1153  0918-6158 2011/08 [Refereed]
  • Atsufumi Kawabata
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 34 (8) 1153 - 1153 0918-6158 2011/08 [Refereed]
  • Atsufumi Kawabata
    BIOLOGICAL & PHARMACEUTICAL BULLETIN PHARMACEUTICAL SOC JAPAN 34 (8) 1170 - 1173 0918-6158 2011/08 [Refereed]
     
    Prostaglandin E-2 (PGE(2)), a cyclooxygenase (COX) product, is the best known lipid mediator that contributes to inflammatory pain. Nonsteroidal anti-inflammatory drugs (NSAIDs), inhibitors of COX-1 and/or COX-2, suppress inflammatory pain by reducing generation of prostanoids, mainly PGE(2), while they exhibit gastrointestinal, renal and cardiovascular toxicities. Selective inhibitors of microsomal PGE synthase-1 and subtype-selective antagonists of PGE(2) receptors, particularly EP1 and EP4, may be useful as analgesics with minimized side-effects. Protein kinase C (PKC) and PKA downstream of EP1 and EP4, respectively, sensitize/activate multiple molecules including transient receptor potential vanilloid-1 (TRPV1) channels, purinergic P2X3 receptors, and voltage-gated calcium or sodium channels in nociceptors, leading to hyperalgesia. PGE(2) is also implicated in neuropathic and visceral pain and in migraine. Thus, PGE(2) has a great impact on pain signals, and pharmacological intervention in upstream and downstream signals of PGE(2) may serve as novel therapeutic strategies for the treatment of intractable pain.
  • K. Okubo; T. Takahashi; F. Sekiguchi; D. Kanaoka; M. Matsunami; T. Ohkubo; J. Yamazaki; N. Fukushima; S. Yoshida; A. Kawabata
    NEUROSCIENCE PERGAMON-ELSEVIER SCIENCE LTD 188 148 - 156 0306-4522 2011/08 
    Hydrogen sulfide (H,S), a gasotransmitter, facilitates pain sensation by targeting Ca(v)3.2 T-type calcium channels. The H(2)S/Ca(v)3.2 pathway appears to play a role in the maintenance of surgically evoked neuropathic pain. Given evidence that chemotherapy-induced neuropathic pain is blocked by ethosuximide, known to block T-type calcium channels, we examined if more selective T-type calcium channel blockers and also inhibitors of cystathionine-gamma-lyase (CSE), a major H(2)S-forming enzyme in the peripheral tissue, are capable of reversing the neuropathic pain evoked by paclitaxel, an anti-cancer drug. It was first demonstrated that T-type calcium channel blockers, NNC 55-0396, known to inhibit Ca(v)3.1, and mibefradil inhibited T-type currents in Ca(v)3.2-transfected HEK293 cells. Repeated systemic administration of paclitaxel caused delayed development of mechanical hyperalgesia, which was reversed by single intraplantar administration of NNC 550396 or mibefradil, and by silencing of Ca(v)3.2 by antisense oligodeoxynucleotides. Systemic administration of DL-propargylglycine and p-cyanoalanine, irreversible and reversible inhibitors of CSE, respectively, also abolished the established neuropathic hyperalgesia. In the paclitaxel-treated rats, upregulation of Ca(v)3.2 and CSE at protein levels was not detected in the dorsal root ganglia (DRG), spinal cord or peripheral tissues including the hindpaws, whereas H(2)S content in hindpaw tissues was significantly elevated. Together, our study demonstrates the effectiveness of NNC 55-0396 in inhibiting Ca(v)3.2, and then suggests that paclitaxel-evoked neuropathic pain might involve the enhanced activity of T-type calcium channels and/or CSE in rats, but not upregulation of Ca(v)3.2 and CSE at protein levels, differing from the previous evidence for the neuropathic pain model induced by spinal nerve cutting in which Ca(v)3.2 was dramatically upregulated in DRG. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
  • Takahiro Miki; Maho Matsunami; Saori Nakamura; Hiroki Okada; Hidekazu Matsuya; Atsufumi Kawabata
    PAIN LIPPINCOTT WILLIAMS & WILKINS 152 (6) 1373 - 1381 0304-3959 2011/06 [Refereed]
     
    Given the previous evidence for involvement of prostanoid EP1 receptors in facilitation of the bladder afferent nerve activity and micturition reflex, the present study investigated the effect of ONO-8130, a selective EP1 receptor antagonist, on cystitis-related bladder pain in mice. Cystitis in mice was produced by intraperitoneal administration of cyclophosphamide at 300 mg/kg. Bladder pain-like nociceptive behavior and referred hyperalgesia were assessed in conscious mice. Phosphorylation of extracellular signal-regulated kinase (ERK) in the L6 spinal cord was determined by immunohistochemistry in anesthetized mice. Cyclophosphamide treatment caused bladder pain-like nociceptive behavior and referred hyperalgesia accompanying cystitis symptoms, including increased bladder weight and vascular permeability and upregulation of cyclooxygenase-2 in the bladder tissue. Oral preadministration of ONO-8130 at 0.3-30 mg/kg strongly prevented both the bladder pain-like behavior and referred hyperalgesia in a dose-dependent manner, but had slight effect on the increased bladder weight and vascular permeability. Oral ONO-8130 at 30 mg/kg also reversed the established cystitis-related bladder pain. Intravesical administration of prostaglandin E-2 caused prompt phosphorylation of ERK in the L6 spinal cord, an effect blocked by ONO-8130. Our findings strongly suggest that the prostaglandin E-2/EP1 system participates in processing of cystitis-related bladder pain, and that EP1 antagonists including ONO-8130 are useful for treatment of bladder pain, particularly in interstitial cystitis. (C) 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
  • M. Matsunami; S. Kirishi; T. Okui; A. Kawabata
    NEUROSCIENCE PERGAMON-ELSEVIER SCIENCE LTD 181 257 - 264 0306-4522 2011/05 [Refereed]
     
    Luminal hydrogen sulfide (H2S) causes colonic pain and referred hyperalgesia in mice through activation of T-type Ca2+ channels. To test a hypothesis that H2S might chelate and remove endogenous Zn2+ that inhibits the Ca(v)3.2 isoform of T-type Ca2+ channels, facilitating visceral nociception, we asked if intracolonic (i.col.) administration of Zn2+ chelators mimics H2S-induced visceral nociception. Visceral nociceptive behavior and referred abdominal allodynia/hyperalgesia were determined after i.col. administration of NaHS, a donor for H2S, or Zn2+ chelators in mice. Phospholylation of extracellular signal-regulated protein kinase (ERK) in the spinal cord was analyzed by immunohistochemistry. The visceral nociceptive behavior and referred abdominal allodynia/hyperalgesia caused by i.col. NaHS in mice were abolished by i.col. preadministration of zinc chloride (ZnCl2), known to selectively inhibit Ca(v)3.2, but not Ca(v)3.1 or Ca-v,3.3, isoforms of T-type Ca2+ channels, and by i.p. preadministration of mibefradil, a pan-T-type Ca2+ channel blocker. Two distinct Zn2+ chelators, N,N,N',N'-tetrakis(2-pyridylmethyl)-ehylenediamine (TPEN) and dipicolinic acid, when administered i.col., mimicked the NaHS-evoked visceral nociceptive behavior and referred abdominal allodynia/hyperalgesia, which were inhibited by mibefradil and by NNC 55-0396, another T-type Ca2+ channel blocker. Like i.col. NaHS, i.col. TPEN caused prompt phosphorylation of ERK in the spinal dorsal horn, an effect blocked by mibefradil. Removal of luminal Zn2+ by H2S and other Zn2+ chelators thus produces colonic pain through activation of T-type Ca2+ channels, most probably of the Cav3.2 isoform. Hence, endogenous Zn2+ is considered to play a critical role in modulating visceral pain. (C) 2011 Published by Elsevier Ltd on behalf of IBRO.
  • Fumiko Sekiguchi; Ai Ohi; Yuma Maeda; Kaori Takaoka; Teruki Sekimoto; Hiroyuki Nishikawa; Atsufumi Kawabata
    JOURNAL OF CELLULAR BIOCHEMISTRY WILEY-BLACKWELL 112 (3) 909 - 915 0730-2312 2011/03 [Refereed]
     
    Proteinase-activated receptor-1 (PAR I), upon activation, exerts prostanoid-dependent gastroprotection, and increases prostaglandin E-2 (PGE(2)) release through cyclooxygenase-2 (COX-2) upregulation in rat gastric mucosal epithelial RGM1 cells. However, there is a big time lag between the PAR I-triggered PG E2 release and COX-2 upregulation in RGM1 cells; that is, the former event takes 18 h to occur, while the latter rapidly develops and reaches a plateau in 6 h. The present study thus aimed at clarifying mechanisms for the delay of PGE2 release after PAR activation in RGM1 cells. Although a PAR1-activating peptide, TFLLR-NH2, alone caused PGE2 release at 18 h, but not 6 h, TFLLR-NH2 in combination with arachidonic acid dramatically enhanced PGE(2) release even for 1-6 h. TFLLR-NH2 plus linoleic acid caused a similar rapid response. CP-24879, a Delta(5)/Delta(6)-desaturase inhibitor, abolished the PGE(2) release induced by TFLLR-NH2 plus linoleic acid, but not by TFLLR-NH2 alone. The TFLLR-NH2-induced PGE2 release was not affected by inhibitors of cytosolic phospholipase A(2) (cPLA(2)), Ca2+-independent PLA(2) (cPLA2) or secretory PLA(2) (sPLA(2)), but was abolished by their mixture or a pan-PLA(2) inhibitor. Among PLA2 isozymes, mRNA of group IIA sPLA(2) (sPLA(2)-IIA) was upregulated following PAR1 stimulation for 6-18 h, whereas protein levels of PGE synthases were unchanged. These data suggest that the delay of PG E2 release after COX-2 upregulation triggered by PAR1 is due to the poor supply of free arachidonic acid at the early stage in RGM1 cells, and that plural isozymes of PLA2 including sPLA2-IIA may complementarily contribute to the liberation of free arachidonic acid. J. Cell. Biochem. 112: 909-915,2011. (C) 2010 Wiley-Liss, Inc.
  • Osamu Fukushima; Sachiyo Nishimura; Maho Matsunami; Yuka Aoki; Hiroyuki Nishikawa; Hiroyasu Ishikura; Atsufumi Kawabata
    JOURNAL OF NEUROSCIENCE RESEARCH WILEY-LISS 88 (14) 3198 - 3205 0360-4012 2010/11 [Refereed]
     
    Noxious stimuli cause prompt phosphorylation of extracellular signal-regulated kinase (ERK) in the spinal dorsal horn that contributes to facilitation of pain sensation and is often used as an immediate marker for excitation of spinal neurons following somatic and colonic nociception. Here we asked whether two distinct pronociceptive stimuli with proteinase-activated receptor-2 (PAR2) agonists and hydrogen sulfide (H(2)S) in the pancreas cause phosphorylation of ERK in the spinal dorsal horn and also examined involvement of their possible downstream signaling molecules, transient receptor potential vanilloid-1 (TRPV1) and T-type Ca(2+) channels, respectively. Capsaicin (a TRPV1 agonist), trypsin (an endogenous PAR2 agonist), SLIGRL-NH(2) (a PAR2-activating peptide), and NaHS (an H2S donor) were infused into the pancreatic duct in anesthetized rats, and phosphorylated ERK in the spinal cord was detected by immunohistochemistry. Intraductal administration of capsaicin and trypsin caused prompt phosphorylation of ERK in the superficial layers of T9, but not T5 or T12, spinal dorsal horn. SLIGRL-NH(2) and NaHS, administered in the same manner, also produced ERK phosphorylation in the corresponding spinal regions. Mibefradil, a T-type Ca(2+) channel blocker, abolished the phosphorylation of ERK caused by intraductal NaHS but not SLIGRL-NH(2). In contrast, capsazepine, an inhibitor of TRPV1, suppressed the phosphorylation of ERK caused by intraductal SLIGRL-NH(2) but not NaHS. Our data thus demonstrate that pancreatic pronociceptive stimuli with PAR2 agonists and H(2)S cause ERK phosphorylation in the spinal dorsal horn, through activation of TRPV1 and T-type Ca(2+) channels, respectively, and that those two pronociceptive pathways are independent of each other. (c) 2010 Wiley-Liss, Inc.
  • Sachiyo Nishimura; Hiroyasu Ishikura; Maho Matsunami; Yui Shinozaki; Fumiko Sekiguchi; Mitsuhide Naruse; Taisuke Kitamura; Ryukichi Akashi; Kenji Matsumura; Atsufumi Kawabata
    LIFE SCIENCES PERGAMON-ELSEVIER SCIENCE LTD 87 (19-22) 643 - 650 0024-3205 2010/11 [Refereed]
     
    Aims: Proteinase-activated receptor-2 (PAR2) and transient receptor potential vanilloid-1 (TRPV1) are co-localized in the primary afferents, and the trans-activation of TRPV1 by PAR2 activation is involved in processing of somatic pain. Given evidence for contribution of PAR2 to pancreatic pain, the present study aimed at clarifying the involvement of TRPV1 in processing of pancreatic pain by the proteinase/PAR2 pathway in mice. Main methods: Acute pancreatitis was created by repeated administration of cerulein in conscious mice, and the referred allodynia/hyperalgesia was assessed using von Frey filaments. Injection of PAR2 agonises into the pancreatic duct was achieved in anesthetized mice, and expression of Fos in the spinal cord was determined by immunohistochemistry. Key findings: The established referred allodynia/hyperalgesia following cerulein treatment was abolished by post-treatment with nafamostat mesilate, a proteinase inhibitor, and with capsazepine, a TRPV1 antagonist, in mice. Injection of trypsin, an endogenous PAR2 agonist, or SLIGRL-NH(2), a PAR2-activating peptide, into the pancreatic duct caused expression of Fos protein in the spinal superficial layers at T8-T10 levels in the mice. The spinal Fos expression caused by trypsin and by SLIGRL-NH(2) was partially blocked by capsazepine, the former effect abolished by nafamostat mesilate. Significance: Our data thus suggest that the proteinase/PAR2/TRPV1 cascade might impact pancreatic pain, in addition to somatic pain, and play a role in the maintenance of pancreatitis-related pain in mice. (C) 2010 Elsevier Inc. All rights reserved.
  • Kazumi Moriyuki; Fumiko Sekiguchi; Kaori Matsubara; Hiroyuki Nishikawa; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 114 (2) 225 - 229 1347-8613 2010/10 [Refereed]
     
    We performed this study to determine if curcumin affects pro-inflammatory responses to activation of proteinase-activated receptor-2 (PAR2) in human pulmonary adenocarcinoma A549 cells. Curcumin completely inhibited the PAR2-triggered prostaglandin E-2 (PGE(2)) production, but notably not interleukin-8 release. Cyclooxygenase-2 (COX-2) upregulation, but not its upstream activation of mitogen-activated protein kinases, caused by PAR2 stimulation was partially inhibited by curcumin. Curcumin inhibited the PAR2-triggered phosphorylation of I-kappa B, an indicator for nuclear factor-kappa B (NF-kappa B) activation, and also its upstream signal Akt, which is known to contribute to PAR2-triggered PGE2 formation, but not COX-2 upregulation. Collectively, curcumin inhibits the PAR2-triggered PGE2 production by suppressing COX-2 upregulation and Akt/NF-kappa B signals in A549 cells.
  • Tomoko Takahashi; Yuka Aoki; Kazumasa Okubo; Yumi Maeda; Fumiko Sekiguchi; Kenji Mitani; Hiroyuki Nishikawa; Atsufumi Kawabata
    PAIN ELSEVIER SCIENCE BV 150 (1) 183 - 191 0304-3959 2010/07 [Refereed]
     
    Hydrogen sulfide (H2S) formed from L-cysteine by multiple enzymes including cystathionine-gamma-lyase (CSE) is now considered a gasotransmitter in the mammalian body. Our previous studies have shown that H2S activates/sensitizes Ca(v)3.2 T-type Ca2+ channels, leading to facilitation of somatic and visceral nociception, and that CSE-derived endogenous H2S participates in inflammatory pain. Here, we show novel evidence for involvement of the endogenous H2S-Ca(v)3.2 pathway in neuropathic pain. In the rat subjected to the right L5 spinal nerve cutting (L5SNC), a neuropathic pain model, i.p. administration of DL-propargylglycine (PPG) and beta-cyanoalanine, irreversible and reversible CSE inhibitors, respectively, strongly suppressed the neuropathic hyperalgesia/allodynia. The anti-hyperalgesic effect of PPG was reversed by intraplantar administration of NaHS, a donor for H2S, in the L5SNC rat. Intraplantar administration or topical application of mibefradil, a T-type Ca2+ channel blocker, reversed hyperalgesia in the L5SNC rat. The protein levels of Ca(v)3.2, but not CSE, in the ipsilateral L4, L5 and L6 dorsal root ganglia were dramatically upregulated in the L5SNC rat. Finally, silencing of Ca(v)3.2 in DRG by repeated intrathecal administration of Ca(v)3.2-targeting siRNA significantly attenuated the neuropathic hyperalgesia in the L5SNC rat. In conclusion, our data suggest that Ca(v)3.2 T-type Ca2+ channels in sensory neurons are upregulated and activated/sensitized by CSE-derived endogenous H2S after spinal nerve injury, contributing to the maintenance of neuropathic pain. We thus propose that Ca(v)3.2 and CSE could be targets for the development of therapeutic drugs for the treatment of neuropathic pain. (C) 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
  • Takeshi Tarui; Kazuki Fukami; Keita Nagasawa; Shigeru Yoshida; Fumiko Sekiguchi; Atsufumi Kawabata
    JOURNAL OF NEUROCHEMISTRY WILEY-BLACKWELL 114 (2) 512 - 519 0022-3042 2010/07 [Refereed]
     
    P>Hydrogen sulfide (H(2)S), a gasotransmitter, induces neuronal differentiation characterized by neuritogenesis and functional up-regulation of high voltage-activated Ca2+ channels, via activation of T-type Ca2+ channels in NG108-15 cells. We thus analyzed signaling mechanisms for the H(2)S-evoked neuronal differentiation. NaHS, a donor for H(2)S, facilitated T-type Ca2+ channel-dependent membrane currents, an effect blocked by ascorbic acid that selectively inhibits Ca(v)3.2 among three T-type channel isoforms. NaHS, applied once at a high concentration (13.5 mM) or repetitively at a relatively low concentration (1.5 mM), as well as ionomycin, a Ca2+ ionophore, evoked neuritogenesis. The neuritogenesis induced by NaHS, but not by ionomycin, was abolished by mibefradil, a T-type Ca2+ channel blocker. PP2, a Src kinase inhibitor, completely suppressed the neuritogenesis caused by NaHS or ionomycin, while it only partially blocked neuritogenesis caused by dibutyryl cAMP, a differentiation inducer. NaHS, but not dibutyryl cAMP, actually caused phosphorylation of Src, an effect blocked by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl, an intracellular Ca2+ chelator, mibefradil or ascorbic acid. The up-regulation of high voltage-activated currents in the cells treated with NaHS was also inhibited by PP2. Together, our data reveal that Src kinase participates in the T-type Ca2+ channel-dependent neuronal differentiation caused by NaHS/H(2)S in NG108-15 cells.
  • Kaori Takaoka; Fumiko Sekiguchi; Hidenori Shigi; Yuma Maeda; Hiroyuki Nishikawa; Atsufumi Kawabata
    TOXICOLOGY ELSEVIER IRELAND LTD 268 (1-2) 40 - 45 0300-483X 2010/01 [Refereed]
     
    Thiazolidinediones, known as peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists, may modify prostaglandin formation and exert gastroprotective effects. Since activation of proteinase-activated receptor-1 (PAR1) reveals endogenous prostanoid-dependent gastroprotection, we investigated if two thiazolidinediones, ciglitazone and troglitazone, modulate the prostaglandin E-2 (PGE(2)) release caused by activation of PAR1 in normal rat gastric mucosal epithelial RGM1 cells. Ciglitazone dramatically facilitated the PAR1-triggered PGE(2) production and cyclooxygenase-2 (COX-2) upregulation, although it had no effect by itself. In contrast, troglitazone suppressed the PARI-triggered PGE2 production and COX-2 upregulation. Either effect of ciglitazone and troglitazone was resistant to GW9662, a PPAR gamma antagonist. The facilitation of the PGE(2) release by ciglitazone was blocked by inhibitors of MEK, p38 MAP kinase (p38MAPK) and PI3-kinase (PI3K), but not JNK. Nonetheless, ciglitazone failed to enhance the PAR1-triggered phosphorylation of ERK and p38MAPK. In conclusion, ciglitazone and troglitazone, exert opposite effects on the PARI-triggered PGE(2) production and COX-2 upregulation by targeting molecules other than PPAR gamma. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
  • Kazumi Moriyuki; Fumiko Sekiguchi; Kaori Matsubara; Hiroyuki Nishikawa; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 111 (3) 269 - 275 1347-8613 2009/11 [Refereed]
     
    Proteinase-activated receptor-2 (PAR2) triggers upregulation of cyclooxygenase-2 (COX-2) and prostaglandin E-2 (PGE(2)) formation in human alveolar epithelial A549 cells. This COX-2 upregulation appears to involve the Src/epidermal growth factor (EGF) receptor/p38 MAP kinase (p38MAPK) pathway and also the cAMP-response element-binding protein (CREB) pathway. Here, we investigated the roles of nuclear factor-kappa B (NF-kappa B)-related signals in the PAR2-triggered PGE(2) release/COX-2 upregulation in A549 cells. The PAR2-triggered PGE2 release was clearly blocked by an inhibitor of the NF-kappa B pathway. Stimulation of PAR2 actually caused phosphorylation of inhibitor-kappa B, an indicator of NF-kappa B activation, an effect being blocked by inhibitors of MEK, phosphatidylinositol 3-kinase (PI3-kinase), and Akt, but little or not by inhibitors of p38MAPK and JNK. Stimulation of PAR2 also caused phosphorylation of Akt, an effect suppressed by inhibitors of PI3-kinase and MEK. Nonetheless, the PAR2-triggered upregulation of COX-2 was resistant to inhibitors of NF-kappa B, PI3-kinase, and Akt, but was attenuated by inhibitors of MEK and JNK. Stimulation of PAR2 induced phosphorylation of CREB, an effect abolished by an inhibitor of MEK but not inhibitors of p38MAPK and EGF receptor. These findings demonstrate that the MEK / ERK / PI3-kinase / Akt / NF-kappa B pathway is involved in PAR2-triggered PGE2 formation, but not upregulation of COX-2 that is dependent on activation of ERK/CREB and JNK in addition to p38MAPK.
  • Kazumi Moriyuki; Fumiko Sekiguchi; Kaori Matsubara; Hiroyuki Nishikawa; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 111 (3) 269 - 275 1347-8613 2009/11 
    Proteinase-activated receptor-2 (PAR2) triggers upregulation of cyclooxygenase-2 (COX-2) and prostaglandin E-2 (PGE(2)) formation in human alveolar epithelial A549 cells. This COX-2 upregulation appears to involve the Src/epidermal growth factor (EGF) receptor/p38 MAP kinase (p38MAPK) pathway and also the cAMP-response element-binding protein (CREB) pathway. Here, we investigated the roles of nuclear factor-kappa B (NF-kappa B)-related signals in the PAR2-triggered PGE(2) release/COX-2 upregulation in A549 cells. The PAR2-triggered PGE2 release was clearly blocked by an inhibitor of the NF-kappa B pathway. Stimulation of PAR2 actually caused phosphorylation of inhibitor-kappa B, an indicator of NF-kappa B activation, an effect being blocked by inhibitors of MEK, phosphatidylinositol 3-kinase (PI3-kinase), and Akt, but little or not by inhibitors of p38MAPK and JNK. Stimulation of PAR2 also caused phosphorylation of Akt, an effect suppressed by inhibitors of PI3-kinase and MEK. Nonetheless, the PAR2-triggered upregulation of COX-2 was resistant to inhibitors of NF-kappa B, PI3-kinase, and Akt, but was attenuated by inhibitors of MEK and JNK. Stimulation of PAR2 induced phosphorylation of CREB, an effect abolished by an inhibitor of MEK but not inhibitors of p38MAPK and EGF receptor. These findings demonstrate that the MEK / ERK / PI3-kinase / Akt / NF-kappa B pathway is involved in PAR2-triggered PGE2 formation, but not upregulation of COX-2 that is dependent on activation of ERK/CREB and JNK in addition to p38MAPK.
  • Eiichi Taniguchi; Maho Matsunami; Takeshi Kimura; Daiki Yonezawa; Tsuyoshi Ishiki; Fumiko Sekiguchi; Hiroyuki Nishikawa; Yuma Maeda; Hiroyasu Ishikura; Atsufumi Kawabata
    TOXICOLOGY ELSEVIER IRELAND LTD 264 (1-2) 96 - 103 0300-483X 2009/10 [Refereed]
     
    Clinical studies suggest that colonic luminal hydrogen sulfide (H(2)S), produced by sulfate-reducing bacteria or through other pathways, might be involved in the pathogenesis of inflammatory bowel disease (IBD). Nonetheless, this hypothesis has been poorly investigated by basic studies using laboratory animals. We thus focused on two enzymes, cystathionine-gamma-lyase (CSE) that generates H(2)S from L-cysteine, and rhodanese that directly or indirectly detoxifies H(2)S, particularly in relation to the colitis induced by dextran sulfate sodium (DSS) in mice. CSE was a major H(2)S-forming enzyme in colonic and renal homogenates from mice and rats, and the rhodanese activity was also detectable in both tissues. Colitis-related symptoms including decreased body weight gain, diarrhea, hematochezia and shortening of colon length were observed in the mice drinking DSS. Those symptoms were not or only slightly attenuated by repeated administration of a CSE inhibitor. CSE activity and protein levels in the colonic tissue did not notably change in the mice with colitis. In contrast, the activity and protein/mRNA levels of rhodanese in the colon, but not kidney, significantly decreased nearly in parallel with the development of colitis, followed by elevation of rhodanese activity in red blood cells (RBCs). These data show that rhodanese, but not CSE, is associated with DSS-induced colitis in mice, leading to a hypothesis that impaired detoxification of H(2)S due to down-regulation or suppression of colonic rhodanese is involved in IBD. The delayed enhancement of rhodanese activity in RBCs, a possible compensative event, might be available as a disease marker for IBD. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
  • Eiichi Taniguchi; Maho Matsunami; Takeshi Kimura; Daiki Yonezawa; Tsuyoshi Ishiki; Fumiko Sekiguchi; Hiroyuki Nishikawa; Yuma Maeda; Hiroyasu Ishikura; Atsufumi Kawabata
    TOXICOLOGY ELSEVIER IRELAND LTD 264 (1-2) 96 - 103 0300-483X 2009/10 
    Clinical studies suggest that colonic luminal hydrogen sulfide (H(2)S), produced by sulfate-reducing bacteria or through other pathways, might be involved in the pathogenesis of inflammatory bowel disease (IBD). Nonetheless, this hypothesis has been poorly investigated by basic studies using laboratory animals. We thus focused on two enzymes, cystathionine-gamma-lyase (CSE) that generates H(2)S from L-cysteine, and rhodanese that directly or indirectly detoxifies H(2)S, particularly in relation to the colitis induced by dextran sulfate sodium (DSS) in mice. CSE was a major H(2)S-forming enzyme in colonic and renal homogenates from mice and rats, and the rhodanese activity was also detectable in both tissues. Colitis-related symptoms including decreased body weight gain, diarrhea, hematochezia and shortening of colon length were observed in the mice drinking DSS. Those symptoms were not or only slightly attenuated by repeated administration of a CSE inhibitor. CSE activity and protein levels in the colonic tissue did not notably change in the mice with colitis. In contrast, the activity and protein/mRNA levels of rhodanese in the colon, but not kidney, significantly decreased nearly in parallel with the development of colitis, followed by elevation of rhodanese activity in red blood cells (RBCs). These data show that rhodanese, but not CSE, is associated with DSS-induced colitis in mice, leading to a hypothesis that impaired detoxification of H(2)S due to down-regulation or suppression of colonic rhodanese is involved in IBD. The delayed enhancement of rhodanese activity in RBCs, a possible compensative event, might be available as a disease marker for IBD. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
  • T. Kanke; M. Kabeya; S. Kubo; S. Kondo; K. Yasuoka; J. Tagashira; H. Ishiwata; M. Saka; T. Furuyama; T. Nishiyama; T. Doi; Y. Hattori; A. Kawabata; M. R. Cunningham; R. Plevin
    BRITISH JOURNAL OF PHARMACOLOGY WILEY-BLACKWELL PUBLISHING, INC 158 (1) 361 - 371 0007-1188 2009/09 
    Background and purpose: Proteinase-activated receptor 2 (PAR(2)) is a G-protein coupled receptor associated with many pathophysiological functions. To date, the development of PAR(2) antagonists has been limited. Here, we identify a number of novel peptide-mimetic PAR(2) antagonists and demonstrate inhibitory effects on PAR(2)-mediated intracellular signalling pathways and vascular responses. Experimental approach: The peptide-mimetic compound library based on the structures of PAR(2) agonist peptides were screened for inhibition of PAR(2)-induced calcium mobilisation in human keratinocytes. Representative compounds were further evaluated by radioligand binding and inhibition of NF kappa B transcriptional activity and IL-8 production. The vascular effects of the antagonists were assessed using in vitro and in vivo models. Key results: Two compounds, K-12940 and K-14585, significantly reduced SLIGKV-induced Ca(2+) mobilisation in primary human keratinocytes. Both K-12940 and K-14585 exhibited competitive inhibition for the binding of a high-affinity radiolabelled PAR(2)-ligand, [(3)H]-2-furoyl-LIGRL-NH(2), to human PAR(2) with K(i) values of 1.94 and 0.627 mu M respectively. NF kappa B reporter activity and IL-8 production were also significantly reduced. Furthermore, relaxation of rat-isolated aorta induced by SLIGRL-NH(2) was inhibited competitively by K-14585. K-14585 also significantly lowered plasma extravasation in the dorsal skin of guinea pigs and reduced salivation in mice. Conclusions and implications: K-12940 and K-14585 antagonized PAR(2) competitively, resulting in inhibition of PAR(2)-mediated signalling and physiological responses both in vitro and in vivo. These peptide-mimetic PAR(2) antagonists could be useful in evaluating PAR(2)-mediated biological events and might lead to a new generation of therapeutically useful antagonists. British Journal of Pharmacology ( 2009) 158, 361-371; doi: 10.1111/j.1476-5381.2009.00342.x
  • S. Nishimura; O. Fukushima; H. Ishikura; T. Takahashi; M. Matsunami; T. Tsujiuchi; F. Sekiguchi; M. Naruse; Y. Kamanaka; A. Kawabata
    GUT B M J PUBLISHING GROUP 58 (6) 762 - 770 0017-5749 2009/06 
    Objective: Hydrogen sulfide (H(2)S) is formed from L-cysteine by multiple enzymes including cystathionine-gamma-lyase (CSE) in mammals, and plays various roles in health and disease. Recently, a pronociceptive role for H(2)S in the processing of somatic pain was identified. Here, the involvement of H(2)S in pancreatic pain is examined. Methods: Anaesthetised rats or mice received an injection of NaHS, a donor for H(2)S, or capsaicin into the pancreatic duct, and the expression of spinal Fos protein was detected by immunohistochemistry. Pancreatitis was created by 6 hourly doses of caerulein in unanaesthetised mice, and pancreatitis-related allodynia/hyperalgesia was evaluated using von Frey hairs. CSE activity and protein levels in pancreatic tissues were measured using the colorimetric method and western blotting, respectively. Results: Either NaHS or capsaicin induced the expression of Fos protein in the superficial layers of the T8 and T9 spinal dorsal horn of rats or mice. The induction of Fos by NaHS but not capsaicin was abolished by mibefradil, a T-type Ca(2+) channel blocker. In conscious mice, repeated doses of caerulein produced pancreatitis accompanied by abdominal allodynia/hyperalgesia. Pretreatment with an inhibitor of CSE prevented the allodynia/hyperalgesia, but not the pancreatitis. A single dose of mibefradil reversed the established pancreatitis-related allodynia/hyperalgesia. Either the activity or protein expression of pancreatic CSE increased after the development of caerulein-induced pancreatitis in mice. Conclusions: The data suggest that pancreatic NaHS/H(2)S most probably targets T-type Ca(2+) channels, leading to nociception, and that endogenous H(2)S produced by CSE and possibly T-type Ca(2+) channels are involved in pancreatitis-related pain.
  • M. Matsunami; T. Tarui; K. Mitani; K. Nagasawa; O. Fukushima; K. Okubo; S. Yoshida; M. Takemura; A. Kawabata
    GUT B M J PUBLISHING GROUP 58 (6) 751 - 761 0017-5749 2009/06 
    Objective: Given recent evidence that hydrogen sulfide (H(2)S), a gasotransmitter, promotes somatic pain through redox modulation of T-type Ca(2+) channels, the roles of colonic luminal H(2)S in visceral nociceptive processing in mice were examined. Methods: After intracolonic administration of NaHS, an H(2)S donor, visceral pain-like behaviour and referred abdominal allodynia/hyperalgesia were evaluated. Phosphorylation of extracellular signal-regulated protein kinase (ERK) in the spinal dorsal horn was determined immunohistochemically. The whole-cell recording technique was used to evaluate T-type Ca(2+) currents (T-currents) in cultured dorsal root ganglion (DRG) neurons. Results: Like capsaicin, NaHS, administered intracolonically at 0.5-5 nmol per mouse, triggered visceral nociceptive behaviour accompanied by referred allodynia/hyperalgesia in mice. Phosphorylation of ERK in the spinal dorsal horn was detected following intracolonic NaHS or capsaicin. The behavioural effects of intracolonic NaHS were abolished by a T-type channel blocker or an oxidant, but not inhibitors of L-type Ca(2+) channels or ATP-sensitive K(+) (K(ATP)) channels. Intraperitoneal NaHS at 60 mu mol/kg facilitated intracolonic capsaicin-evoked visceral nociception, an effect abolished by the T-type channel blocker, although it alone produced no behavioural effect. In DRG neurons, T-currents were enhanced by NaHS. Conclusions: These findings suggest that colonic luminal H(2)S/NaHS plays pronociceptive roles, and imply that the underlying mechanisms might involve sensitisation/activation of T-type channels probably in the primary afferents, aside from the issue of the selectivity of mibefradil.
  • 気体メディエーターとしての硫化水素の神経機能
    川畑 篤史
    脳21 12 (12) 239 - 245 2009/04
  • Yumi Maeda; Yuka Aoki; Fumiko Sekiguchi; Maho Matsunami; Tomoko Takahashi; Hiroyuki Nishikawa; Atsufumi Kawabata
    PAIN ELSEVIER SCIENCE BV 142 (1-2) 127 - 132 0304-3959 2009/03 [Refereed]
     
    Hydrogen sulfide (H2S), a gasotransmitter, facilitates membrane currents through T-type Ca2+ channels, and intraplantar (i.pl.) administration of NaHS, a donor of H2S, causes prompt hyperalgesia in rats. In this. context, we asked whether intrathecal (i.t.) administration of NaHS could mimic the hyperalgesic effect of i.pl. NaHS in rats, and then examined if Ca(v)3.2 isoform of T-type Ca2+ channels contributed to the pronociceptive effects of i.t. and i.pl. NaHS. Either i.t. or i.pl. administration of NaHS rapidly decreased nociceptive threshold in rats, as determined by the paw pressure method. The hyperalgesia caused by i.t. and i.pl. NaHS was abolished by co-administration of mibefradil, a pan-T-type Ca2+ channel inhibitor, and also Suppressed by pretreatment with i.t. and i.pl, zinc chloride, known to preferentially inhibit Ca(v)3.2 among T-type Ca2+ channel isoforms, respectively. Repeated i.t. administration of antisense oligodeoxynucleotides (ODNs) targeting rat Cav3.2, but not mismatch ODNs, caused silencing of Ca(v)3.2 protein in the dorsal root ganglia and spinal cord, and then attenuated the hyperalgesia induced by either i.t. or i.pl, NaHS. Our findings thus establish that spinal and peripheral NaHS/H2S activates or sensitizes Ca(v)3.2 T-type Ca2+ channels expressed in the primary afferents and/or spinal nociceptive neurons, leading to sensitization of nociceptive processing and hyperalgesia. (C) 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
  • Keita Nagasawa; Takeshi Tarui; Shigeru Yoshida; Fumiko Sekiguchi; Maho Matsunami; Ai Ohi; Kazuki Fukami; Seiji Ichida; Hiroyuki Nishikawa; Atsufumi Kawabata
    JOURNAL OF NEUROCHEMISTRY WILEY-BLACKWELL 108 (3) 676 - 684 0022-3042 2009/02 [Refereed]
     
    We investigated if stimulation of T-type Ca2+ channels with sodium hydrosulfide (NaHS), a donor of hydrogen sulfide (H2S), could cause neuronal differentiation of NG108-15 cells. Like dibutyryl cyclic AMP (db-cAMP), treatment with NaHS at 1.5-13.5 mM for 16 h enhanced neurite outgrowth in a concentration-dependent manner. Synergistic neuritogenic effect was obtained in the cells stimulated with NaHS in combination with db-cAMP at subeffective concentrations. Exposure to NaHS or db-cAMP for 2 days resulted in enhancement of expression of high-voltage-activated currents consisting of N-, P/Q-, L- and also other types, but not of T-type currents. Mibefradil, a pan-T-type channel blocker, abolished the neuritogenesis induced by NaHS, but not by db-cAMP. The NaHS-evoked neuritogenesis was also completely blocked by pretreatment with BAPTA/AM, a chelator of intracellular Ca2+, and by zinc chloride at a concentration known to selectively inhibit Ca(v)3.2 isoform of T-type Ca2+ channels, but not Ca(v)3.1 or Ca(v)3.3. Further, l-ascorbate, recently proven to selectively inhibit Ca(v)3.2, abolished the neuritogenic effect of NaHS, but not db-cAMP. Our data thus demonstrate that NaHS/H2S is a novel inducer of neuronal differentiation in NG108-15 cells, as characterized by neuritogenesis and expression of high-voltage-activated currents, and suggest the involvement of T-type Ca2+ channels, especially Ca(v)3.2.
  • Yusuke Tanaka; Fumiko Sekiguchi; Hao Hong; Atsufumi Kawabata
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ACADEMIC PRESS INC ELSEVIER SCIENCE 377 (2) 622 - 626 0006-291X 2008/12 [Refereed]
     
    Proteinase-activated receptor-2 (PAR2) plays pro-inflammatory roles in many organs including the gastrointestinal (GI) tract. To clarify the downstream pro-inflammatory signaling of PAR2 in the GI tract, we examined interleukin-8 (IL-8) release and the underlying cellular signaling following PAR2 stimulation in human colorectal cancer-derived HCT-15 cells and human gastric adenocarcinoma-derived MKN-45 cells. A PAR2-activating peptide, but not a PAR2-inactive scrambled peptide or a PAR1 - activating peptide, caused IL-8 elease in these GI epithelial cells. The PAR2-triggered IL-8 release was suppressed by inhibitors of MEK (U0126) or PI3-kinase (LY294002), and PAR2 stimulation indeed activated the downstream kinases, ERK and Akt. U0126 blocked the phosphorylation of ERK, but not Akt, and LY294002 blocked the phosphorylation of Akt, but not ERK. Together, PAR2 triggers IL-8 release via two independent signaling pathways, MEK/ERK and PI3-kinase/Akt, suggesting a role of PAR2 as a pro-inflammatory receptor in the GI tract. (C) 2008 Elsevier Inc. All rights reserved.
  • Katsuya Hirano; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 108 (4) 406 - 407 1347-8613 2008/12 [Refereed]
  • Protease-activated receptor シグナル
    関口 富美子; 川畑 篤史
    救急・集中治療 20 (9-10) 1297 - 1303 2008/11
  • Mami Nagataki; Kazumi Moriyuki; Fumiko Sekiguchi; Atsufumi Kawabata
    CELL BIOCHEMISTRY AND FUNCTION JOHN WILEY & SONS LTD 26 (2) 279 - 282 0263-6484 2008/03 [Refereed]
     
    We investigated possible involvement of three isozymes of prostaglandin E synthase (PGES), microsomal PGES-1 (mPGES-1), mPGES-2 and cytosolic PGES (cPGES) in COX-2-dependent prostaglandin E-2 (PGE(2)) formation following proteinase-activated receptor-2 (PAR2) stimulation in human lung epithelial cells. PAR2 stimulation up-regulated mPGES-1 as well as COX-2, but not mPGES-2 or cPGES, leading to PGE2 formation. The PAR2-triggered up-regulation of mPGES-1 was suppressed by inhibitors of COX-1, cytosolic phospholipase A(2) (cPLA(2)) and MEK, but not COX-2. Finally, a selective inhibitor of mPGES-1 strongly suppressed the PAR2-evoked PGE(2) formation. PAR2 thus appears to trigger specific up-regulation of mPGES-1 that is dependent on prostanoids formed via the MEK/ERK/cPLA(2)/COX-1 pathway, being critical for PGE(2) formation. Copyright (c) 2007 John Wiley & Sons, Ltd.
  • A. Kawabata; M. Matsunami; F. Sekiguchi
    BRITISH JOURNAL OF PHARMACOLOGY NATURE PUBLISHING GROUP 153 S230 - S240 0007-1188 2008/03 
    It has been almost a decade since the molecular cloning of all four members of the proteinase-activated receptor ( PAR) family was completed. This unique family of G protein-coupled receptors (GPCRs) mediates specific cellular actions of various endogenous proteinases including thrombin, trypsin, tryptase, etc. and also certain exogenous enzymes. Increasing evidence has been clarifying the emerging roles played by PARs in health and disease. PARs, particularly PAR1 and PAR2, are distributed throughout the gastrointestinal (GI) tract, modulating various GI functions. One of the most important GI functions of PARs is regulation of exocrine secretion in the salivary glands, pancreas and GI mucosal epithelium. PARs also modulate motility of GI smooth muscle, involving multiple mechanisms. PAR2 appears to play dual roles in pancreatitis and related pain, being pro-inflammatory/pro-nociceptive and anti-inflammatory/anti-nociceptive. Similarly, dual roles for PAR1 and PAR2 have been demonstrated in mucosal inflammation/damage throughout the GI tract. There is also fundamental and clinical evidence for involvement of PAR2 in colonic pain. PARs are thus considered key molecules in regulation of GI functions and targets for development of drugs for treatment of various GI diseases.
  • Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 106 47P - 47P 1347-8613 2008 [Refereed]
  • Tomoko Takahashi; Yumi Maeda; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 106 63P - 63P 1347-8613 2008 [Refereed]
  • Hitomi Hayashi; Satoko Kubo; Hiroyuki Nishikawa; Fumiko Sekiguchi; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 106 95P - 95P 1347-8613 2008 [Refereed]
  • Yusuke Tanaka; Hao Hong; Fumiko Sekiguchi; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 106 101P - 101P 1347-8613 2008 [Refereed]
  • Satoko Kubo; Hitomi Hayashi; Hiroyuki Nishikawa; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 106 169P - 169P 1347-8613 2008 [Refereed]
  • Furniko Sekiguchi; Ai Ohi; Kaori Takaoka; Hiroyuki Nishikawa; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 106 211P - 211P 1347-8613 2008 [Refereed]
  • Kaori Takaoka; Hidenori Shigi; Fumiko Sekiguchi; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 106 211P - 211P 1347-8613 2008 [Refereed]
  • Kazumi Moriyuki; Mami Nagataki; Fumiko Sekiguchi; Hiroyuki Nishikawa; Atsufumi Kawabata
    REGULATORY PEPTIDES ELSEVIER SCIENCE BV 145 (1-3) 42 - 48 0167-0115 2008/01 [Refereed]
     
    Proteinase-activated receptor-2 (PAR2) plays a dual role in the respiratory system, being pro- and anti-inflammatory. In human lung epithelial cells (A549), PAR2 activation causes release of interleukin-8 (IL-8) in addition to prostaglandin E-2 (PGE(2)). In the present study, we thus investigated PAR2-triggered signal transduction pathways causing IL-8 formation in A549 cells. SLIGRL-NH2, a PAR2-activating peptide, but not LSIGRL-NH2,, a scrambled peptide, elicited release of IL-8 from A549 cells for 18 h, as measured by the ELISA method, an effect being suppressed by inhibitors of MEK, JNK, EGF receptor-tyrosine kinase (EGFR-TK), Src, pan-tyrosine kinases and protein kinase C, but not p38 MAP kinase or cyclooxygenase. SLIGRL-NH2, also up-regulated IL-8 at protein and mRNA levels, as determined by Western blotting and RTPCR, respectively. The PAR2-triggered up-regulation of IL-8 protein and mRNA was blocked by an inhibitor of MEK, but not clearly by inhibitors of JNK and EGFR-TK. SLIGRL-NH2 actually phosphorylated JNK as well as ERK, the JNK activation being resistant to inhibitors of Src, pan-tyrosine kinases, protein kinase C and EGFR-TK. Our data suggest that PAR2-triggerd IL-8 formation involves transcriptional upregulation of IL-8 via the MEK-ERK pathway, while the JNK and EGF receptor pathways might rather contribute to a post-transcriptional process for the release of IL-8. (c) 2007 Elsevier B.V. All rights reserved.
  • S. Kubo; M. Kajiwara; A. Kawabata
    Inflammopharmacology 15 (6) 288 - 292 0925-4692 2007/12 
    To clarify roles of H2S in regulation of gastric circulation, we investigated effects of NaHS, a H2S donor, on tension of isolated rat gastric artery and gastric mucosal blood flow in rats. In the precontracted ring preparations, NaHS caused contraction and relaxation at low and high concentrations, respectively. The NaHS-induced vasorelaxation was only partially blocked by glibenclamide, a K+ ATP channel inhibitor. The contractile activity of NaHS disappeared by removal of the endothelium or by inhibition of nitric oxide synthase and the endothelium-derived hyperpolarizing factor (EDHF) pathways. Intravenous injection of NaHS caused transient increase followed by decrease in gastric mucosal blood flow in rats. Collectively, in the gastric artery, NaHS appears to cause relaxation through both K+ ATP channel-dependent and -independent pathways and contraction through inhibition of NO and EDHF pathways. Together with the in vivo results, our study implies that H2S plays multiple complex roles in regulation of gastric circulation. © 2007 Springer.
  • F. Sekiguchi; K. Takaoka; A. Kawabata
    Inflammopharmacology 15 (6) 246 - 251 0925-4692 2007/12 
    Proteinase-activated receptors (PARs), G protein-coupled receptors, play critical roles in the alimentary system. Increasing evidence suggests that endogenous prostaglandins (PGs) mediate some of PARs' gastrointestinal functions. Systemic administration of the PAR1 agonist protects against gastric mucosal injury through PG formation in rats. PGs also appear to contribute, at least in part, to enhancement of gastric mucosal blood flow and suppression of gastric acid secretion by PAR1 activation. There is also evidence for involvement of PGs in modulation of gastrointestinal motility by PAR1 or PAR2. Importantly, modulation of ion transport by PAR1 or PAR2 in the intestinal mucosal epithelium is largely mediated by PGs. Studies using gastric and intestinal mucosal epithelial cell lines imply that the PAR1-triggered formation of PGs involves multiple signaling pathways including Src, EGF receptor trans-activation and activation of MAP kinases. Collectively, a functional linkage of PAR1 and/or PAR2 to PGs is considered important in the gastrointestinal system. © 2007 Springer.
  • Atoko Kubo; Yuko Kurokawa; Ichiko Doe; Takashi Masuko; Fumiko Sekiguchi; Atsufumi Kawabata
    TOXICOLOGY ELSEVIER IRELAND LTD 241 (1-2) 92 - 97 0300-483X 2007/11 [Refereed]
     
    To clarify the presence of cross-talk between H2S and NO, we investigated effect of NaHS, an H2S donor, on activity of recombinant NO synthase (NOS) isoforms. Activity of all nNOS, iNOS and eNOS was inhibited by NaHS (IC50: 0.13-0.21 mM). In contrast, Na2SO3, L-Cysteine and threo-1,4-dimercapto-2,3-butanediol, a reductant, exerted poor inhibition of NOS activity. Increasing concentrations of tetrahydrobiopterin (BH4) reversed the NaHS inhibition of nNOS and eNOS, but not iNOS. Our data thus demonstrate inhibition of three NOS isoforms by NaHS/H2S, and suggest involvement of interaction of NaHS/H2S with BH4 in inhibition of nNOS and eNOS, but not iNOS. (C) 2007 Elsevier Ireland Ltd. All rights reserved.
  • 松波 真帆; 川畑 篤史
    日本薬理学雑誌 130 (5) 436 - 437 0015-5691 2007/11
  • Daiki Yonezawa; Fumiko Sekiguchi; Misato Miyamoto; Eiichi Taniguchi; Masami Honjo; Takashi Masuko; Hiroyuki Nishikawa; Atsufumi Kawabata
    TOXICOLOGY ELSEVIER IRELAND LTD 241 (1-2) 11 - 18 0300-483X 2007/11 [Refereed]
     
    We investigated effect of hydrogen sulfide (H2S) on oxidative stress-caused cell death in gastric mucosal epithelial cells. In rat normal gastric epithelial RGM1 cells, NaHS, a H2S donor, at 1.5 mM strongly suppressed hydrogen peroxide (H2O2)-caused cell death, while it slightly augmented the H2O2 toxicity at 0.5-1 mM. The protective effect of NaHS was abolished by inhibitors of MEK or JNK, but not of p38 MAP kinase. NaHS at 1.5 mM actually phosphorylated ERK and JNK in RGM1 cells. Glibenclamide, an ATP-sensitive K+ (K-ATP(+)) channel inhibitor, did not affect the protective effect of NaHS, although mRNAs for K(ATP)(+)channel subunits, Kir6.1 and SUR1, were detected in RGM1 cells. In anesthetized rats, oral administration of NaHS protected against gastric mucosal lesion caused by ischemia-reperfusion. These results suggest that NaHS/H2S may protect gastric mucosal epithelial cells against oxidative stress through stimulation of MAP kinase pathways, a therapeutic dose range being very narrow. (C) 2007 Elsevier Ireland Ltd. All rights reserved.
  • Atsufumi Kawabata; Tsuyoshi Ishiki; Kelta Nagasawa; Shigeru Yoshida; Yumi Maeda; Tomoko Takahashi; Fumiko Sekiguchi; Tetsuyuki Wada; Seiji Ichida; Hiroyuki Nishikawa
    PAIN ELSEVIER SCIENCE BV 132 (1-2) 74 - 81 0304-3959 2007/11 [Refereed]
     
    Hydrogen sulfide (H2S), an endogenous gasotransmitter, modulates various biological events such as inflammation in the mammalian body. The present study investigated possible involvement of H2S in peripheral nociceptive processing. Intraplantar (i.pl.) administration of NaHS, a H2S donor, produced prompt hyperalgesia in rats, accompanied by expression of Fos in the spinal dorsal horn. The H2S-evoked hyperalgesia was blocked by 5,5'-dithio-bis-(2-nitrobenzoic acid) (DTNB), an oxidizing agent, or ethosuximide and mibefradil, T-type Ca2+ channel inhibitors. L-Cysteine, an endogenous source for H2S, given i.pl., also elicited hyperalgesia, an effect being abolished by DL-propargylglycine (PPG) and beta-cyanoalanine (BCA), inhibitors of cystathionine-gamma-lyase, a H2S synthesizing enzyme. PPG and/or BCA partially inhibited the hyperalgesia induced by i.pl. lipopolysaccharide, an effect being reversed by i.pl. NaHS. In the patch-clamp study using undifferentiated NG108-15 cells that express T-type, but not other types, of Ca2+ channels, NaHS enhanced the currents through the T-type channels, an effect being blocked by DTNB. Thus, H2S appears to function as a novel nociceptive messenger through sensitization of T-type Ca2+ channels in the peripheral tissues, particularly during inflammation. (C) 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
  • Atsufumi Kawabata
    PAIN ELSEVIER SCIENCE BV 130 (3) 302 - 303 0304-3959 2007/08
  • Satoko Kubo; Ichiko Doe; Yuko Kurokawa; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 104 (4) 392 - 396 1347-8613 2007/08 [Refereed]
     
    We investigated the effects of NaHS, a hydrogen sulfide (H2S) donor, on the tension of isolated mouse and guinea-pig bronchial rings. NaHS at 0.01-10 mM had no effect on the tone of those preparations without precontraction. When the preparation was precontracted with carbachol, NaHS at 0.1-3 mM strongly relaxed the mouse rings, but produced only slight relaxation in the guinea-pig rings. The NaHS-induced relaxation in the mouse bronchus was resistant to inhibitors of ATP-sensitive K+ channels, soluble guanylyl cyclase, cyclooxygenase (COX)-1 or COX-2, and antagonists of tachykinin receptors. Thus, NaHS evokes bronchodilation in mice, suggesting a possible role for H2S in the respiratory system.
  • Hiroyasu Ishikura; Sachiyo Nishimura; Maho Matsunami; Toshifumi Tsujiuchi; Tsuyoshi Ishiki; Fumiko Sekiguchi; Mitsuhide Naruse; Toshio Nakatani; Yoshihisa Kamanaka; Atsufumi Kawabata
    LIFE SCIENCES PERGAMON-ELSEVIER SCIENCE LTD 80 (21) 1999 - 2004 0024-3205 2007/05 [Refereed]
     
    Camostat mesilate, an orally available proteinase inhibitor, is clinically used for treatment of pancreatitis. Given recent evidence that pancreatic proteinases including trypsin and/or proteinase-activated receptor-2 (PAR2) might be involved in pancreatic pain, we examined if camostat mesilate could suppress spinal Fos expression, a marker for neuronal activation, following specific application of trypsin to the pancreas, and pancreatitis-related referred allodynia. Trypsin, administered into the pancreatic duct, caused delayed expression of Fos proteins in the superficial layer of the bilateral T8 and T9 spinal dorsal horns in rats. The trypsin-induced spinal Fos expression was completely abolished by oral preadministration of camostat mesilate at 300 mg/kg. After hourly repeated (6 times in total) administration of caerulein, mice showed typical symptoms of pancreatitis, accompanied by mechanical allodynia in the upper abdomen (i.e., referred hyperalgesia/allodynia), as assessed by use of von Frey filaments. Camostat mesilate at 100-300 mg/kg, given orally twice before the 1st and 4th doses of cacrulein, abolished the pancreatitis-related abdominal allodynia, while it partially prevented the inflammatory signs. The same doses of camostat mesilate, when administered once after the final dose of caerulein, also revealed significant anti-allodynic effect. These data suggest that camostat mesilate prevents and/or depresses pancreatitis-induced pain and/or referred hyperalgesia/allodynia, in which proteinases including trypsin would play a critical role. (C) 2007 Elsevier Inc. All rights reserved.
  • Satoko Kubo; Ichiko Doe; Yuko Kurokawa; Hiroyuki Nishikawa; Atsufumi Kawabata
    TOXICOLOGY ELSEVIER IRELAND LTD 232 (1-2) 138 - 146 0300-483X 2007/03 [Refereed]
     
    We characterized actions of hydrogen sulfide (H2S) on tension of isolated rat and mouse aortae, and then examined if H2S could directly modulate activity of endothelial nitric oxide (NO) synthase (eNOS). Isometric tension was recorded in rat and mouse aortic rings. Activity of recombinant bovine eNOS was determined as conversion of [H-3]-arginine into [H-3]-citrulline. NaHS, a H2S donor, caused contraction at low concentrations and relaxation at high concentrations in both rat and mouse aortae precontracted with phenylephrine. The contractile and relaxant effects of NaHS were enhanced and partially blocked, respectively, by the K-ATP(+) channel inhibitor glibenclamide in the rat, but not mouse, aortae. In the KCl-precontracted rat aorta, NaHS produced glibenclamide-resistant contraction and relaxation. NaHS produced only relaxation, but not contraction, in the endothelium-denuded aortae, and also in the endothelium-intact aortae in the presence of inhibitors of NOS or soluble guanylate cyclase. NaHS pretreatment greatly attenuated the relaxation induced by acetylcholine, but not by an NO donor, in the tissues. Finally, we found that NaHS inhibited the conversion of [H-3]-arginine into [H-3]-citrulline by recombinant eNOS. NaHS thus causes contraction and relaxation in rat and mouse aortae. K-ATP(+) channels are considered to contribute only partially to the NaHS-evoked relaxation. Most interestingly, our data demonstrate direct inhibition of eNOS by NaHS, probably responsible for its contractile activity, being evidence for a novel function of H2S. (c) 2007 Elsevier Ireland Ltd. All rights reserved.
  • Tomoko Takahashi; Takeshi Tarui; Kenji Mitami; Keita Nagasawa; Yumi Maeda; Shigeru Yoshida; Atsufumi Kawabata
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 127 144 - 147 0031-6903 2007 [Refereed]
     
    Injury or dysfunction of the peripheral and central nervous systems is often associated with neuropathic pain. Although a large number of studies have been made on the mechanism of neuropathic pain, the detail of mechanism is still unclear. Hydrogen sulfide (H2S) is now being considered an endogenous gasotransmitter in the mammalian body. Most recently, we have revealed that H2S participates in peripheral nociceptive processing through activation of T-type Ca2+ channels. Here we show that systemic administration of an inhibitor of H2S-synthesizing enzyme attenuates hyperalgesia/allodynia in a rat model for neuropathic pain, an effect being reversed by intraplantar administration of an H2S donor. Thus, endogenous H2S might be involved in neuropathic pain.
  • Fumiko Sekiguchi; Satoko Kubo; Yuko Kurokawa; Hitomi Hayahi; Hiroyuki Nishikawa; Yukari Okamoto; Atsufumi Kawabata
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 127 89 - 92 0031-6903 2007 [Refereed]
     
    Hydrogen sulfide (H2S), the third gaseous mediator following nitric oxide (NO) and carbon monoxide, modulates various physiological functions in the mammalian body. Here we analyzed and characterized roles for H2S in modulation of smooth muscle motility. In precontracted aortic rings prepared from rats and mice, NaHS, a donor of H2S, induced contraction at low concentrations and relaxation at high concentrations. The NaHS-induced relaxation involved both ATP-sensitive K+ (KATP) channel-dependent and -independent pathways in rat aorta, but was independent of KATP channels in mouse aorta. The NaHS-induced contraction was attributable to direct inhibition of endothelial NO synthase by NaHS. NaHS at high concentrations also caused KATP channel-independent relaxation in airway and gastrointestinal smooth muscle preparations from rats, mice or guinea-pigs. Together, H2S modulates smooth muscle motility through multiple mechanisms, being excitative and suppressive.
  • Takeshi Tarui; Keita Nagasawa; Nobuyuki Fukushima; Hiroyuki Nishikawa; Atsufumi Kawabata
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN PHARMACEUTICAL SOC JAPAN 127 163 - 165 0031-6903 2007 [Refereed]
     
    Thrombin modulates neuronal functions via proteinase-activated receptors (PARs) in the CNS. In the present study, we examined effect of a human plasma-derived thrombin reagent (hp-thrombin) on neurite outgrowth in a rat pheochromocytoma cell line, PC12. Although it alone had no effect, hp-thrombin promoted NGF-induced neurite outgrowth in PC12 cells. This effect was neither inhibited by hirudin, a specific inhibitor of thrombin, and nor mimicked by receptor-activating peptides for PARI or PAR4. In addition, human recombinant thrombin did not cause facilitation of neurite outgrowth. Finally, the effect of hp-thrombin on NGF-evoked neurite outgrowth was specifically blocked by a Src-selective tyrosine kinase inhibitor. Collectively, unknown bioactive contaminants in hp-thrombin appear to facilitate neurite outgrowth, an indicator for neural differentiation, and the underlying mechanisms would involve activation of Src kinase.
  • Fumiko Sekiguchi; Shino Saito; Kaori Takaoka; Hitomi Hayashi; Mami Nagataki; Keita Nagasawa; Hiroyuki Nishikawa; Hirofumi Matsui; Atsufumi Kawabata
    BIOCHEMICAL PHARMACOLOGY PERGAMON-ELSEVIER SCIENCE LTD 73 (1) 103 - 114 0006-2952 2007/01 [Refereed]
     
    Proteinase-activated receptor-1 (PAR1), a thrombin receptor, plays a protective role in gastric mucosa via prostanoid formation. Thus, we studied effects of PAR1 stimulation on prostaglandin E-2 (PGE(2)) formation in rat normal gastric mucosal epithelial RGM1 cells and analyzed the underlying signal transduction mechanisms. The PARI-activating peptide (PAR1-AP) and thrombin increased PGE(2) release from RGM1 cells for 18 h, an effect being suppressed by inhibitors of COX-1, COX-2, MEK, p38 MAP kinase (p38 MAPK), protein kinase C (PKC), Src and EGF receptor-tyrosine kinase (EGFR-TK), but not JNK and matrix metalloproteinase (MMP)/a disintegrin and metalloprotemases (ADAMs). PAR1-AP caused persistent (6 h or more) and transient (5 min) phosphorylation of ERK and p38 MAPK, respectively, followed by delayed reinforcement at 18 h. PAR1-AP up-regulated COX-2 in a manner dependent on MEK and EGFR-TK, but not p38 MAPK. The PARI-mediated persistent ERK phosphorylation was reduced by inhibitors of Src and EGFR-TK. PAR1-AP actually phosphorylated EGF receptors and up-regulated mRNA for heparin-binding-EGF (HB-EGF), the latter effect being blocked by inhibitors of Src, EGFR-TK and MEK. Heparin, an inhibitor for HB-EGF, suppressed PAR1-mediated PGE2 formation and persistent ERK phosphorylation. These results suggest that PAR1 up-regulates COX-2 via persistent activation of MEK/ERK that is dependent on EGFR-TK activation following induction of HB-EGF, leading to PGE(2) formation. In addition, our data also indicate involvement of COX-1, PKC and p38 MAPK in PAR1-triggered PGE(2) formation. PAR1, thus stimulates complex multiple signaling pathways responsible for PGE(2) formation in RGM1 cells. (c) 2006 Elsevier Inc. All rights reserved.
  • Matsunami M; Sekiguchi T; Kawabata A
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica 128 (6) 434 - 436 0015-5691 2006/12 [Refereed]
  • MATSUNAMI Maho; SEKIGUCHI Fumiko; KAWABATA Atsufumi
    Folia pharmacologica Japonica 日本薬理学会 128 (6) 434 - 436 0015-5691 2006/12
  • Kawabata A
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica The Japanese Pharmacological Society 128 (2) 82 - 87 0015-5691 2006/08 [Refereed]
     
    Proteinase-activated receptor（PAR）は，特定のセリンプロテアーゼによって活性化されるGタンパク共役7回膜貫通型受容体であり，PAR1，PAR2，PAR3，PAR4の4つのファミリーメンバーが知られている．これらのPARは消化器系臓器全般に広く発現し，多様な役割を演じている．PAR2およびPAR1はいずれも胃粘膜において種々の機能の制御に関与し，第一義的には粘膜保護の方向に働いているが，その機能メカニズムは大きく異なっている．消化管平滑筋運動調節においてPARは抑制的な面と促進的な面を併せ持ち，その機能の特性やメカニズムは動物種や臓器部位によって大きく異なる．またPAR2は内臓痛および腸炎症の発現，さらに外分泌機能の調節にも関与している．このように，PARの消化管機能は複雑であるが，PARアゴニストあるいはアンタゴニストは，胃粘膜傷害のほか，消化管運動・内臓痛覚の異常に関連する過敏性腸症候群，炎症性腸疾患などの治療にも利用できる可能性があり，今後，特に臨床応用の面における研究の進歩が期待される．
  • Atsufumi Kawabata; Naoyuki Kawao; Yoshimi Hironaka; Tsuyoshi Ishiki; Maho Matsunami; Fumiko Sekiguchi
    NEUROPHARMACOLOGY PERGAMON-ELSEVIER SCIENCE LTD 51 (2) 182 - 190 0028-3908 2006/08 [Refereed]
     
    Bisphosphonates, pyrophosphate analogues, known as inhibitors of bone resorption, appear to cause analgesia in certain clinical painful situations. To detect clinically relevant analgesic property of etidronate, a non-aminobisphosphonate, we examined and characterized its antiallodynic effect in the rat with adjuvant-induced arthritis, in comparison with alendronate, an aminobisphosphonate, as determined by the von Frey test. Repeated systemic administration of etidronate at 10-40 mg/kg/day suppressed the adjuvant-induced mechanical allodynia in rat hindpaw, an effect reaching a plateau in approximately 10 days. Systemic or intraplantar (i.pl.) administration of ATP-sensitive K+ (K-ATP(+)) channel inhibitors, glibenclamide and/or tolbutamide, completely reversed the antiallodynic effect of etidronate within 1 h in the arthritic rats, without affecting the nociceptive scores in naive or arthritic animals that had not received etidronate. Alendronate, administered repeatedly, also revealed similar glibenclamide-reversible antiallodynic effect. In contrast, the antiallodynic effect of repeated systemic indomethacin was resistant to i.pl. glibenclamide in the arthritic rats. Repeated administration of etidronate or alendronate only slightly attenuated the adjuvant-evoked hindpaw edema. Among K-ATP(+) channel subunits, mRNAs for Kir6.1, SUR1, SUR2A and SUR2B were abundant in rat dorsal root ganglia, while Kir6.2 mRNA was poor. Our data demonstrate that repeated etidronate as well as alendronate exhibits antiallodynic activity in arthritic rats, which might be clinically relevant, and suggest involvement of K-ATP(+) channels in the underlying mechanisms. (c) 2006 Elsevier Ltd. All rights reserved.
  • KAWABATA Atsufumi
    Folia Pharmacologica Japonica The Japanese Pharmacological Society 127 (3) 133 - 136 0015-5691 2006/08 
    Protease-activated receptor-2（PAR-2）は，トリプシン，トリプターゼなどの特定のセリンプロテアーゼの細胞への作用を媒介するGタンパク共役型受容体である．PAR-2は知覚神経C線維ニューロンに発現し，炎症性疼痛や熱痛覚過敏の発現に関与している．また，PAR-2は内臓痛の情報伝達・制御にも重要な役割を演じている．結腸内腔側に存在すると考えられるPAR-2の活性化により，遅発性の内臓痛覚過敏が誘起される．一方，PAR-2は膵臓では痛みに対して促進的な面と抑制的な面を併せ持つ．このように，PAR-2は痛みの情報伝達制御に関与する新たな生体内分子として，創薬の面からも興味がもたれている．
  • 川畑 篤史
    日薬理誌 128 82 - 87 2006/08
  • A Kawabata; N Kawao; T Kitano; M Matsunami; R Satoh; T Ishiki; T Masuko; T Kanke; N Saito
    NEUROSCIENCE LETTERS ELSEVIER IRELAND LTD 402 (1-2) 167 - 172 0304-3940 2006/07 [Refereed]
     
    Intracolonic (i.col.) administration of the PAR2-activating peptide (PAR2AP) SLIGRL-NH2 Slowly develops visceral hypersensitivity to i.col. capsaicin in ddY mice. Thus, we further analyzed roles of PAR2 in colonic hypersensitivity, using the novel potent PAR2AP, 2-furoyl-LIGRL-NH2 and PAR2-knockout (KO) mice. In ddY mice, i.col. 2-furoyl-LIGRL-NH2 produced delayed (6 h later) facilitation of capsaicin-evoked visceral nociception, an effect,being much more potent than SLIGRL-NH2. Such effects were mimicked by i.col. trypsin. In wild-type (WT), but not PAR2-KO, mice of C57BL/6 background, i.col. PAR2 agonists caused delayed facilitation of sensitivity to capsaicin. The PAR2-triggered visceral hypersensitivity was abolished by a bradykinin B2 receptor antagonist, HOE-140. Our data thus provide ultimate evidence for role of PAR2 in colonic hypersensitivity, and suggest involvement of the bradykinin-B2 pathway. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
  • A Kawabata; M Matsunami; M Tsutsumi; T Ishiki; O Fukushima; F Sekiguchi; N Kawao; T Minami; T Kanke; N Saito
    BRITISH JOURNAL OF PHARMACOLOGY NATURE PUBLISHING GROUP 148 (1) 54 - 60 0007-1188 2006/05 [Refereed]
     
    1 Proteinase-activated receptor-2 (PAR2), a receptor activated by trypsin and tryptase, is abundantly expressed in the gastrointestinal tract including the C-fiber terminal, and might play a role in processing of visceral pain. In the present study, we examined and characterized the roles of PAR2 in pancreatitis-related abdominal hyperalgesia/allodynia in mice. 2 Caerulein, administered i.p. once, caused a small increase in abdominal sensitivity to stimulation with von Frey hairs, without causing pancreatitis, in PAR2-knockout (KO) mice, but not wild-type (WT) mice. 3 Caerulein, given hourly six times in total, caused more profound abdominal hyperalgesia/allodynia in PAR2-KO mice, as compared with WT mice, although no significant differences were detected in the severity of pancreatitis between the KO and WT animals. 4 The PAR2-activating peptide, 2-furoyl-LIGRL-NH2, coadministered repeatedly with caerulein six times in total, abolished the caerulein-evoked abdominal hyperalgesia/allodynia in WT, but not PAR2-KO, mice. Repeated doses of 2-furoyl-LIGRL-NH2 moderately attenuated the severity of caerulein-induced pancreatitis in WT animals. 5 Our data from experiments using PAR2-KO mice provide evidence that PAR2 functions to attenuate pancreatitis-related abdominal hyperalgesia/allodynia without affecting pancreatitis itself, although the PAR2AP applied exogenously is not only antinociceptive but also anti-inflammatory.
  • Kawabata A
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica The Japanese Pharmacological Society 127 (3) 133 - 6, 146 0015-5691 2006/03 [Refereed]
     
    Protease-activated receptor-2（PAR-2）は，トリプシン，トリプターゼなどの特定のセリンプロテアーゼの細胞への作用を媒介するGタンパク共役型受容体である．PAR-2は知覚神経C線維ニューロンに発現し，炎症性疼痛や熱痛覚過敏の発現に関与している．また，PAR-2は内臓痛の情報伝達・制御にも重要な役割を演じている．結腸内腔側に存在すると考えられるPAR-2の活性化により，遅発性の内臓痛覚過敏が誘起される．一方，PAR-2は膵臓では痛みに対して促進的な面と抑制的な面を併せ持つ．このように，PAR-2は痛みの情報伝達制御に関与する新たな生体内分子として，創薬の面からも興味がもたれている．
  • F Sekiguchi; N Hasegawa; K Inoshita; D Yonezawa; N Inoi; T Kanke; N Saito; A Kawabata
    LIFE SCIENCES PERGAMON-ELSEVIER SCIENCE LTD 78 (9) 950 - 957 0024-3205 2006/01 [Refereed]
     
    Proteinase-activated receptor (PAR)-1 or -2 modulates gastrointestinal transit in vivo. To clarify the underlying mechanisms, we characterized contraction/relaxation caused by TFLLR-NH2 and SLIGRL-NH2, PAR-1- and -2-activating peptides, respectively, in gastric and small intestinal (duodenal, jejunal and ileal) smooth muscle isolated from wild-type and PAR-2-knockout mice. Either SLIGRL-NH2 or TFLLR-NH2 caused both relaxation and contraction in the gastrointestinal preparations from wild-type animals. Apamin, a K+ channel inhibitor, tended to enhance the peptide-evoked contraction in some of the gastrointestinal preparations, whereas it inhibited relaxation responses to either peptide completely in the stomach, but only partially in the small intestine. Indomethacin reduced the contraction caused by SLIGRL-NH2 or TFLLR-NH2 in both gastric and ileal preparations, but unaffected apamin-insensitive relaxant effect of either peptide in ileal preparations. Repeated treatment with capsaicin suppressed the contractile effect of either peptide in the stomach, but not clearly in the ileum, whereas it enhanced the apamin-insensitive relaxant effect in ileal preparations. In any gastrointestinal preparations from PAR-2-knockout mice, SLIGRL-NH2, produced no responses. Thus, the inhibitory component in tension modulation by PAR-1 and -2 involves both apamin-sensitive and -insensitive mechanisms in the small intestine, but is predominantly attributable to the former mechanism in the stomach. The excitatory component in the PAR-1 and -2 modulation may be mediated, in part, by activation of capsaicin-sensitive sensory nerves and/or endogenous prostaglandin formation. Our study thus clarifies the multiple mechanisms for gastrointestinal motility modulation by PAR-1 and -2, and also provides ultimate evidence for involvement of PAR-2. (c) 2005 Elsevier Inc. All rights reserved.
  • Satoko Kubo; Tsuyoshi Ishiki; Ichiko Doe; Fumiko Sekiguchi; Hiroyuki Nishikawa; Kenzo Kawai; Hirofumi Matsui; Atsufumi Kawabata
    SIGNAL TRANSDUCTION PATHWAYS, PT B BLACKWELL PUBLISHING 1091 445 - 459 0077-8923 2006 [Refereed]
     
    Proteinase-activa ted receptor-1 (PAR1), a G protein-coupled receptor (GPCR) for thrombin, can be activated not only by PARlactivating peptides (PAR1APs) based on the N-terminal cryptic tethered ligand sequence but also by an N-palmitoylated (Pal) peptide, Pal-RCLSSSAVANRSKKSRALF-amide (P1pal-19), based on the intracellular loop 3 of PARI, designated pepducin, in human platelets or PAR1-transfected cells. The present article evaluated the actions of P1pal-19 and also the shorter peptide, Pal-RCLSSSAVANRS-amide (P1pal-12), known as a possible PAR1 antagonist, in multiple cells/tissues that naturally express PAR1. P1pal-19 as well as a PAR1AP, TFLLR-amide, evoked cytosolic Ca2+ mobilization in cultured human lung epithelial cells (A549) and rat gastric mucosal epithelial cells (RGM1). P1pal-19 and TFLLR-amide, but not a PAR2-activating peptide, SLIGRL-amide, caused delayed prostaglandin E-2 formation in RGM1 cells. P1pal-19, like TFLLR-amide, produced endothelial NO-dependent relaxation in rat aorta and epithelial prostanoid-dependent relaxation in mouse bronchus. The P1pal-19-induced relaxation remained constant even after desensitization of PARI with TFLLR-amide in either tissue. P1pal-19 failed to mimic the contractile effects of TFLLR-amide in the endothelium-denuded preparations of rat aorta or superior mesenteric artery and the rat gastric longitudinal smooth muscle strips. P1pal12 partially inhibited the vasorelaxation caused by TFLLR-amide and P1pal-19, but not SLIGRL-amide, in the rat. aorta. Our data thus indicate that P1pal-19 is capable of mimicking the effects of PAR1APs in the endothelial and epithelial, but not smooth muscle, cells/tissues, and suggest that P1pal-12 may act as a PAR1 antagonist in the vascular endothelium.
  • T Kanke; T Takizawa; M Kabeya; A Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 97 (1) 38 - 42 1347-8613 2005/01 [Refereed]
     
    PAR-2 is the second member of the family of proteinase-activated receptors activated by trypsin, tryptase, and several other serine proteinases. In order to evaluate the therapeutic potential for PAR-2, we have performed studies on PAR-2-mediated signal transduction and investigated the effects of PAR-2 gene deficiency in disease models. In addition to the G-protein-coupled receptor-mediated common signal transduction pathways, inositol 1,4,5-trisphosphate production and mobilization of Ca2+, PAR-2 can also activate multiple kinase pathways, EPK, p38MAPK, JNK, and IKK, in a cell-type specific manner. The studies using PAR-2-gene-deficient mice highlighted critical roles of PAR-2 in progression of skin and joint inflammation. We also describe the development and evaluation of potent and metabolically stable PAR-2 agonists in multiple assay systems both in vitro and in vivo. The structure-activity relationship analysis indicated the improved potencies of furoylated peptides. Furthermore, the resistance of the furoylated peptide against aminopeptidase contributed to the highly potent and sustained effects of the peptide in vivo. These studies suggest the potential therapeutic importance of PAR-2 in inflammatory diseases. Also, the PAR-2-gene-deficient mice and the potent and metabolically stable agonists are shown to be useful tools for evaluating the potency of PAR-2 as a therapeutic target.
  • A Kawabata; Y Oono; D Yonezawa; K Hiramatsu; N Inoi; F Sekiguchi; M Honjo; M Hirofuchi; T Kanke; H Ishiwata
    BRITISH JOURNAL OF PHARMACOLOGY NATURE PUBLISHING GROUP 144 (2) 212 - 219 0007-1188 2005/01 [Refereed]
     
    1 Proteinase-activated receptor-2 (PAR(2)), expressed in capsaicin-sensitive sensory neurons, plays a protective role in gastric mucosa. The present study evaluated gastric mucosal cytoprotective effect of 2-furoyl-LIGRL-NH2, a novel highly potent PAR(2) agonist, in ddY mice and in wild-type and PAR(2)-knockout mice of C57BL/6 background. 2 Gastric mucosal injury was created by oral administration of HCl/ethanol solution in the mice. The native PAR(2)-activating peptide SLIGRL-NH2, administered intraperitoneally (i.p.) at 0.3 - 1 mumol kg(-1) in combination with amastatin, an aminopeptidase inhibitor, but not alone, revealed gastric mucosal protection in ddY mice, which was abolished by ablation of capsaicin-sensitive sensory neurons. 3 I.p. administration of 2-furoyl-LIGRL-NH2 at 0.1 mumol kg(-1), without combined treatment with amastatin, exhibited gastric mucosal cytoprotective activity in ddY mice, the potency being much greater than SLIGRL-NH2 in combination with amastatin. This effect was also inhibited by capsaicin pretreatment. 4 Oral administration of 2-furoyl-LIGRL-NH2 at 0.003 - 0.03 mumol kg(-1) also protected against gastric mucosal lesion in a capsaicin-reversible manner in ddY mice. 5 I.p. 2-furoyl-LIGRL-NH2 at 0.1 - 0.3 mumol kg(-1) caused prompt salivation in anesthetized mice, whereas its oral administration at 0.003 - 1 mumol kg(-1) was incapable of eliciting salivation. 6 In wild-type, but not PAR(2)-knockout, mice of C57BL/6 background, i.p. administration of 2-furoyl-LIGRL-NH2 caused gastric mucosal protection. 7 Thus, 2-furoyl-LIGRL-NH2 is considered a potent and orally available gastric mucosal protective agent. Our data also substantiate a role for PAR2 in gastric mucosal protection and the selective nature of 2-furoyl-LIGRL-NH2.
  • F Sekiguchi; Y Mita; Y Kamanaka; N Kawao; H Matsuya; C Taga; A Kawabata
    NEUROSCIENCE LETTERS ELSEVIER IRELAND LTD 365 (2) 111 - 115 0304-3940 2004/07 [Refereed]
     
    We evaluated if ONO-1714, known as an inducible nitric oxide synthase (iNOS) inhibitor, could inhibit neuronal NOS (nNOS) and exert antinociception. ONO-1714 potently inhibited both crude rat cerebellar NOS and recombinant human nNOS in vitro. Systemic ONO-1714 at 1-10 mg/kg suppressed carrageenan-induced thermal hyperalgesia in rats, an effect being equivalent to the antinociception caused by L-NAME or 7-nitroindazole at 25 m/kg. The same doses of ONO-1714 also caused hypertension. Intrathecal (j.t.) ONO-1714 potently reduced the hyperalgesia. the effective dose range (0.2-0.6 mug/rat) being much lower than the antinociceptive dose (150 mug/rat) of i.t. L-NAME. Thus, ONO-1714 is considered a potent inhibitor of nNOS in addition to iNOS. The distinct relative antinociceptive activities of systemic and i.t. ONO-1714 are attributable to its possible poor blood-brain barrier permeability. (C) 2004 Elsevier Ireland Ltd. All rights reserved.
  • A Kawabata; N Kawao; H Itoh; C Shimada; K Takebe; R Kuroda; T Masuko; K Kataoka; S Ogawa
    NEUROSCIENCE LETTERS ELSEVIER SCI IRELAND LTD 329 (3) 349 - 353 0304-3940 2002/09 [Refereed]
     
    Activation of the peripheral protease-activated receptor-2 (PAR-2) triggers nociceptive behaviour and thermal hyperalgesia in rats. The present study created a novel mouse model for PAR-2-triggered nociception, and then examined the roles of NMIDA receptors and the nitric oxide (NO) pathway in nociceptive processing by PAR-2. Intraplantar administration of the PAR-2 agonist SLIGRL-NH2 elicited nociceptive responses in mice, an effect being more specific in mast cell-depleted mice. This PAR-2-triggered nociception was abolished by the NMDA receptor antagonist MK-801, but not the neuronal NO synthase inhibitor 7-nitro indazole. In contrast, the PAR-2-triggered thermal hyperalgesia in rats was blocked by both agents. Our study thus provides a novel mouse model for PAR-2-mediated nociception, and suggests that NMDA receptors are involved in PAR-2-triggered nociception and hyperalgesia, while NO contributes only to the latter. (C) 2002 Published by Elsevier Science Ireland Ltd.
  • A Kawabata; M Kinoshita; R Kuroda; K Kakehi
    CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY BLACKWELL PUBLISHING ASIA 29 (4) 360 - 361 0305-1870 2002/04 [Refereed]
     
    1. Protease-activated receptor 2 (PAR2), present in capsaicin-sensitive sensory neurons, induces gastric mucus secretion and mucosal cytoprotection. 2. We studied the possible cross-talk between PAR2 and vanilloid receptor 1 (VR1). The VR1 antagonist capsazepine partially inhibited the PAR2-mediated increase in gastric mucus secretion. 3. Thus, activation of VR1 is responsible, at least in part, for the neurally mediated mucosal cytoprotection following activation of PAR2.
  • N Kawao; Y Sakaguchi; A Tagome; R Kuroda; S Nishida; K Irimajiri; H Nishikawa; K Kawai; MD Hollenberg; A Kawabata
    BRITISH JOURNAL OF PHARMACOLOGY NATURE PUBLISHING GROUP 135 (5) 1292 - 1296 0007-1188 2002/03 [Refereed]
     
    1 Agonists of protease-activated receptor-2 (PAR-2) trigger neurally mediated mucus secretion accompanied by mucosal cytoprotection in the stomach. The present study immunolocalized PAR-2 in the rat gastric mucosa and examined if PAR-2 could modulate pepsin/pepsinogen secretion in rats. 2 PAR-2-like immunoreactivity was abundant in the deep regions of gastric mucosa, especially in chief cells. 3 The PAR-2 agonist SLIGRL-NH2, but not the control peptide LSIGRL-NH2 adininistered i.v. repeatedly at 0.3-1 mumol kg(-1), four times in total, significantly facilitated gastric pepsin secretion, although a single dose produced no significant effect. 4 The PAR-2-mediated gastric pepsin secretion was resistant to omeprazole, N-G-nitro-L-arginine methyl ester (L-NAME) or atropine, and also to ablation of sensory neurons by capsaicin. 5 Our study thus provides novel evidence that PAR-2 is localized in mucosal chief cells and facilitates gastric pepsin secretion in the rats. most probably by a direct mechanism. British Journal of Pharmacology (2002).
  • A Kawabata; N Kawao; R Kuroda; H Itoh; H Nishikawa
    NEUROREPORT LIPPINCOTT WILLIAMS & WILKINS 13 (4) 511 - 514 0959-4965 2002/03 [Refereed]
     
    Protease-activated receptor-2 (PAR-2) in the sensory neurons may be involved in nociceptive processing. We attempted to detect and characterize specific expression of spinal Fos, a marker of nociception, in mast cell-depleted rats. Intraplantar (i.pl) administration of not only the PAR-2 agonist SLIGRL-NH2, but also the control peptide LSIGRL-NH2, induced Fos expression in naive rats, whereas only the former specifically produced Fos expression in mast cell-depleted rats. This Fos expression was blocked by intrathecal DAMG0, a mu-opioid agonist, and, in part, by i.pl. calphostin C, a protein kinase C (PKC) inhibitor. Thus, specific expression of spinal Fos following peripheral PAR-2 activation is detectable in mast cell-depleted rats, suggesting activation of spinal nociceptive neurons, which is partially mediated by activation of PKC.
  • Atsufumi Kawabata; Ryotaro Kuroda
    Folia Pharmacologica Japonica 120 (1) 85P - 87P 0015-5691 2002 [Refereed]
     
    Protease-activated receptor-2 (PAR-2), a G protein-coupled seven trans-membrane domain receptor, is distributed throughout the gastrointestinal tract, modulating various functions. In gastric mucosa, PAR-2 present in sensory neurons, upon activation, triggers mucus secretion by stimulating release of CGRP and tachykinins, resulting mucosal cytoprotection. PAR-2 activation also suppresses acid secretion and increases mucosal blood flow, contributing to the protective mechanisms. In contrast, PAR-2 is also present in chief cells, facilitating pepsinogen secretion. PAR-2 would thus appear to be primarily protective in gastric mucosa, but may also have an aggressive property in certain conditions. Finally, functions of PARs other than PAR-2 in gastric mucosa are also discussed.
  • ラット胃粘膜におけるG蛋白共役型プロテアーゼ受容体PAR-2の局在とペプシン分泌への影響
    河尾 直之; 坂口 祐里子; 田込 あい; 西田 升三; 西川 裕之; 入交 清博; 荒木 宏昌; Hollenberg Morley D.; 黒田 良太郎; 川畑 篤史
    日本薬理学雑誌 (公社)日本薬理学会 118 (4) 21P - 21P 0015-5691 2001/10
  • Atsufumi Kawabata; Ryotaro Kuroda; Morley D. Hollenberg
    Folia Pharmacologica Japonica 114 (1) 0015-5691 1999 [Refereed]
     
    The protease-activated receptor (PAR), a G protein-coupled receptor present on cell surface, mediates cellular actions of extracellular proteases. Proteases cleave the extracellular N-terminal of PAR molecules at a specific site, unmasking and exposing a novel N-terminal, a tethered ligand, that binds to the body of receptor molecules resulting in receptor activation. Amongst four distinct PARs that have been cloned, PARs 1,3 and 4 are activated by thrombin, but PAR-2 is activated by trypsin or mast cell tryptase. Human platelets express two distinct thrombin receptors, PAR-1 and PAR-4, while murine platelets express PAR-3 and PAR-4. Apart from roles of PARs in platelet activation, PARs are distributed to a number of organs in various species, predicting their physiological importance. We have been evaluating agonists specific for each PAR, using multiple procedures including a HEK cell calcium signal receptor desensitization assay. Using specific agonists that we developed, we found the following: 1) the salivary glands express PAR-2 mRNA and secret saliva in response to PAR-2 activation 2) pancreatic juice secretion occurs following in vivo PAR-2 activation 3) PAR-1 and PAR-2 modulate duodenal motility. Collectively, PAR plays various physiological and/or pathophysiological roles, especially in the digestive systems, and could be a novel target for drug development.
  • A KAWABATA; H TAKAGI
    NITRIC OXIDE JAPAN SCIENTIFIC SOC PRESS (17) 115 - 125 1994 [Refereed]

Books etc

  • H2S and pain: a novel aspect for processing of somatic, visceral and neuropathic pain signals. In Chemistry, Biochemistry and Pharmacology of Hydrogen Sulfide, edited by Moore, P.K. and Whiteman, M.
    Terada, Y; Kawabata, A (Joint work)Springer 2015 217-230
  • 香月 博志; 成田 年; 川畑 篤史 廣川書店 2015 9784567495103 xviii, 662p
  • Disseminated intravascular coagulation (DIC)-like events produced by environmental stress and by lipopolysaccharide : Nitric oxide as a common key molecule.
    The Biology of Nitric Oxide Part 6(Portland Press, London) 1998
  • NOの疼痛制御における役割の多様性
    医学のあゆみ別冊「NOのすべて」 1996
  • Multiplicity of the role of nitric oxide in pain modulation
    1996
  • NOと痛み
    NO(メジカルビュー社) 1995
  • 痛みの情報伝達・制御とNO
    NO研究の最前線(実験医学・増刊号)(羊土社) 1995
  • NO and Pain(共著)
    NO 1995
  • The Role of NO in Pain Processing(共著)
    Nitric Oxide (Experimental Medicine) 1995
  • The dual role of L-arginine in nociceptive processing in the brain : involvement of nitric oxide and kyotorphin(共著)
    Nitric Oxide-Roles in Neuronal Communication and Neurotoxicity (Japan Scientific Societies Press, and CRC Press) 1994

Conference Activities & Talks

  • 活性化protein Cはproteinases-activated receptor 1 を介して神経障害性疼痛を抑制する
    圓尾賢悟; 池田裕哉; 坪田真帆; 王登莉; 西堀正洋; 南達郎; 伊藤彰敏; 川畑篤史
    第96回日本薬理学会年会
  • 定型抗精神病薬pimozideの構造展開により開発した新規T型Ca2+チャネル阻害薬KTtp38：チャネル選択性、電気生理学的特徴、鎮痛活性の評価
    笠波嘉人; 高島康宏; 木野貴博; 石川千浩; 長南百香; 豊岡尚樹; 関口富美子; 坪田真帆; 川瀬篤史; 大久保つや子; 吉田 繁; 岡田卓哉; 川畑篤史
    第96回日本薬理学会年会
  • マウスにおける補体アナフィラトキシンC5a誘起アロディニアの発現メカニズムについて
    田島和樹; 圓尾賢悟; 坪田真帆; 王登莉; 西堀正洋; 南達郎; 伊藤彰敏; 川畑篤史
    第96回日本薬理学会年会
  • H2SおよびATP補捉作用を有するrepagermanium (Ge-132) はマウスにおけるパクリタキセル誘発性末梢神経障害を抑制する
    関口富美子; 安達義史; 島田康弘; 中村宜司; 川畑篤史
    第96回日本薬理学会年会
  • オキサリプラチン誘起末梢神経障害（OIPN）への血小板由来HMGB1の関与：抗血小板薬のOIPN予防効果について
    岸本彩野; 堂本莉紗; 松永浩明; 松本亜紗菜; 坪田真帆; 関口富美子; 王登莉; 西堀正洋; 川畑篤史
    第96回日本薬理学会年会
  • 創薬と薬物療法適正化に向けた臨床薬学と薬理学の統合的研究アプローチ
    川畑篤史
    第96回日本薬理学会年会
  • 活性化プロテインCは神経障害性疼痛を抑制する：Proteinase-activated receptor-1（PAR1）の関与について
    圓尾賢悟; 池田裕哉; 坪田真帆; 王登莉; 西堀正洋; 南達郎; 伊藤彰敏; 川畑篤史
    生体機能と創薬シンポジウム2022
  • アンギオテンシン変換酵素阻害薬とアンギオテンシンII受容体拮抗薬は糖尿病性末梢神経障害の発症を抑制する：臨床・基礎融合研究によるエビデンス
    冨田詩織; 宮本朋佳; 田中雅幸; 打谷和記; 小泉祐一; 村中達也; 根本亙; 丹野孝一; 坪田真帆; 関口富美子; 川畑篤史
    生体機能と創薬シンポジウム2022
  • Oxaliplatin誘起末梢神経障害には血小板由来HMGB1が関与する
    岸本彩野; 堂本莉紗; 松永浩明; 松本亜紗菜; 坪田真帆; 関口富美子; 王登莉; 西堀正洋; 川畑篤史
    第141回日本薬理学会近畿部会  2022/07
  • 井場祐里子、本夛泉侑、坪田真帆、川瀬篤史、岡田卓哉、豊岡尚樹、川畑篤史
    芳香族L-アミノ酸脱炭酸酵素を阻害しないD-carbidopaはH; 産生酵素cystathionine-β-synthaseを阻害することでTNBS誘起結腸痛を抑制する
    第141回日本薬理学会近畿部会  2022/07
  • レセプトデータを用いたpotentially inappropriate medications (PIMs)の実態調査：認知症患者において特に注意を要するPIMs処方について
    笠波嘉人; 山本卓資; 宮本朋佳; 松野純男; 榊原幹夫; 岩城正宏; 川畑篤史
    日本薬学会第142年会
  • Butyrate誘起結腸過敏におけるマクロファージおよび腸管グリア由来HMGB1の役割
    佐々木花菜; Shin Eunkyung; 野中結; 坪田真帆; Wang Dengli; 西堀正洋; 川畑篤史
    日本薬学会第142年会
  • 抗がん剤vincristineおよびbortezomibにより誘起される末梢神経障害に関与するマクロファージからのHMGB1遊離メカニズムの相違
    青木葉優衣; 谷津健太; 池田裕哉; 関口富美子; 坪田真帆; Wang Dengli; 西堀正洋; 川畑 篤史
    日本薬学会第142年会
  • 糖尿病性末梢神経障害はthrombin依存的にthrombomodulin alfaによって抑制され抗凝固薬によって増悪する：基礎・臨床融合研究による新知見
    冨田詩織; 中野遥; 坪田真帆; 田中雅幸; 打谷和記; 村中達也; 川畑篤史
    第95回日本薬理学会年会
  • 抗リウマチ薬sulfasalazineはToll-like receptor 4刺激によるマクロファージからのHMGB1遊離を抑制することで炎症性疼痛を軽減する
    堂本莉紗; 田村ひなの; 関口富美子; 坪田真帆; 西堀正洋; 川畑篤史
    第95回日本薬理学会年会
  • ポリサルファイドはサルファイドのCav3.2 T型Ca2+チャネル機能亢進作用を再現できない：亜鉛親和性の相違が関与する可能性について
    笠波嘉人; 南郷優希; 増田寛志; 関口富美子; 大久保つや子; 吉田 繁; 川畑篤史
    第95回日本薬理学会年会
  • Thrombomodulin/thrombin系で産生されるTAFIa/carboxypeptidase Bは補体成分C5aを不活性化することでoxaliplatin誘発性末梢神経障害を抑制する
    圓尾賢悟; 坪田真帆; 田島和樹; 関口富美子; 西堀正洋; 南 達郎; 伊藤彰敏; 川畑篤史
    第95回日本薬理学会年会
  • AGE拮抗薬azeliragonはヒト前立腺がん由来LNCaP細胞の生存・増殖を抑制する：影響をうける細胞シグナルの解析
    芝野奈帆; 安達義史; 脇谷航平; 浅野絵莉茄; 関口富美子; 岡田卓哉; 西川裕之; 豊岡尚樹; 川畑篤史
    第95回日本薬理学会年会
  • 内因性H2S産生阻害による多発性骨髄腫細胞の生存抑制: カルビドパとベンセラジドのcystathionine-β-synthase阻害活性とボルテゾミブ耐性多発性骨髄腫治療への応用について
    関口富美子; 森口晴香; 福島志歩; 井場祐里子; 坪田真帆; 平本志於里; 岡田卓哉; 豊岡尚樹; 田中宏和; 芦田隆司; 松村到; 川畑篤史
    第95回日本薬理学会年会
  • サルファイドによるCav3.2依存性疼痛と有機ゲルマニウムの効果
    関口富美子; 増田寛志; 笠波嘉人; 小池寧々; 南郷優希; 島田康弘; 松本果歩; 佐藤克行; 中村宜司; 山口浩明; 田邉元三; 丸本真輔; 坪田真帆; 川畑篤史
    痛み研究会（2021年度）  2022/01
  • 抗リウマチ薬sulfasalazineはマクロファージからのHMGB1遊離を抑制することでlipopolysaccharide誘起アロディニアを抑制する
    堂本莉紗; 田村ひなの; 関口富美子; 坪田真帆; 西堀正洋; 川畑篤史
    第140回日本薬理学会近畿部会  2021/11
  • Cav3.2 T型Ca2+チャネルの機能におよぼすサルファイドとポリサルファイドの異なる効果：亜鉛の果たす役割について
    笠波嘉人; 南郷優希; 増田寛志; 関口富美; 大久保つや子; 吉田 繁; 川畑篤史
    第140回日本薬理学会近畿部会  2021/11
  • Thrombomodulin alfaのoxaliplatin誘発性末梢神経障害抑制作用発現におけるHMGB1不活性化とprotein C及びTAFI活性化の相対的重要性と下流シグナル分子の解析
    圓尾賢悟; 坪田真帆; 田島和樹; 関口富美子; 西堀正洋; 南 達郎; 伊藤彰敏; 川畑篤史
    第140回日本薬理学会近畿部会  2021/11
  • オキサリプラチン誘起末梢神経障害の発症メカニズムの解析―HMGB1および内因性トロンボモジュリン/トロンビンの役割―  [Invited]
    坪田真帆、川畑篤史
    第71回日本薬学会関西支部総会・大会  2021/10  東大阪
  • 芳香族Lアミノ酸脱炭酸酵素阻害薬カルビドパはH2S産生酵素cystathionine-β-synthaseを阻害することで内臓痛を抑制する  [Not invited]
    井場祐里子、本夛泉侑、坪田真帆、川瀬篤史、岩城正宏、川畑篤史
    第71回日本薬学会関西支部総会・大会  2021/10  東大阪
  • 芳香族Lアミノ酸脱炭酸酵素阻害薬カルビドパとベンセラジドは多発性骨髄腫細胞の生存・増殖を抑制する：H2S産生阻害作用の関与について  [Not invited]
    森口晴香、関口富美子、福島志歩、本夛泉侑、井場祐里子、坪田真帆、平本志於里、田中宏和、芦田隆司、松村到、川畑篤史
    第71回日本薬学会関西支部総会・大会  2021/10  東大阪
  • プロテアソーム阻害薬はマクロファージからカスパーゼ依存性にHMGB1を遊離させる：多発性骨髄腫治療薬ボルテゾミブ誘発性末梢神経障害への関与について  [Not invited]
    青木葉優衣、池田裕哉、関口富美子、坪田真帆、川畑篤史
    第71回日本薬学会関西支部総会・大会  2021/10  東大阪
  • トロンボモジュリンアルファは2型糖尿病db/dbマウスにおける有痛性末梢神経障害をトロンビン依存性に抑制する：ストレプトゾシン誘発1型糖尿病モデルとの違いについて  [Not invited]
    中野遥、冨田詩織、坪田真帆、川畑篤史
    第71回日本薬学会関西支部総会・大会  2021/10  東大阪
  • オキサリプラチン誘起末梢神経障害への補体C5aの関与  [Not invited]
    田島和樹、圓尾賢悟、坪田真帆、西堀正洋、川畑篤史
    第71回日本薬学会関西支部総会・大会  2021/10  東大阪
  • サルファイドによるCav3.2 T型Ca2+チャネル機能増強メカニズムの解析：ポリサルファイドとの違いと亜鉛の関与  [Not invited]
    南郷優希、増田寛志、笠波嘉人、関口富美子、大久保つや子、吉田 繁、川畑篤史
    第71回日本薬学会関西支部総会・大会  2021/10  東大阪（大阪）
  • Cav3.2 T型Ca2+チャネルおよびHMGB1の役割  [Not invited]
    坪田真帆、川畑篤史
    生体機能と創薬シンポジウム2021  2021/08  札幌 (ハイフレックス)
  • Thrombomodulin alfaによるoxaliplatin誘起末梢神経障害発症抑制作用に関与するメカニズムの解析：HMGB1不活性化作用とprotein C及びTAFI活性化作用の寄与について  [Not invited]
    圓尾賢悟、田島和樹、坪田真帆、西堀正洋、川畑篤史
    生体機能と創薬シンポジウム2021  2021/08  札幌 (ハイフレックス)
  • Butyrate誘起過敏性腸症候群モデルにおける結腸過敏へのマクロファージおよび腸管グリア細胞由来HMGB1の関与  [Not invited]
    佐々木花菜、Shin Eunkyung、野中結、梶谷梨絵、坪田真帆、西堀正洋、川畑篤史
    生体機能と創薬シンポジウム2021  2021/08  札幌 (ハイフレックス)
  • エストロゲンはマクロファージからのHMGB1遊離とHMGB1感受性を低下させることでパクリタキセル誘発性末梢神経障害を抑制的に制御する  [Not invited]
    貫戸綾乃、坪田真帆、平本志於里、松永浩明、宮本朋佳、小泉祐一、西堀正洋、川畑篤史
    生体機能と創薬シンポジウム2021  2021/08  札幌 (ハイフレックス)
  • T型カルシウムチャネル阻害活性を有する定型抗精神病薬pimozideの構造展開研究による新規難治性疼痛治療薬の創製  [Not invited]
    笠波嘉人、木野貴博、石川千浩、高島康宏、長南百香、岡田卓哉、関口富美子、吉田 繁、大久保つや子、豊岡尚樹、川畑篤史
    生体機能と創薬シンポジウム2021  2021/08  札幌 (ハイフレックス)
  • エストロゲンはマクロファージにおけるパクリタキセル誘起HMGB1遊離とマウスにおけるHMGB1誘起アロディニアを抑制する：エストロゲン低下によるパクリタキセル誘発性末梢神経障害重症化との関係について  [Not invited]
    貫戸綾乃、坪田真帆、平本志於里、松永浩明、宮本朋佳、小泉祐一、西堀正洋、川畑篤史
    第139回日本薬理学会近畿部会  2021/06  名古屋（リモート）
  • H2S産生酵素cystathionine-β-synthaseの阻害薬はボルテゾミブ耐性を獲得した多発性骨髄腫細胞の生存・増殖を抑制する  [Not invited]
    関口富美子、福島志歩、森口晴香、平本志於里、田中宏和、芦田隆司、松村到、川畑篤史
    第139回日本薬理学会近畿部会  2021/06  名古屋（リモート）
  • H2S供与体Na2Sのマウス頬皮内投与により誘起されるCav3.2依存性掻痒および疼痛に対する定型抗精神病薬pimozideとD2受容体遮断活性を減弱させた新規pimozide誘導体KTtp-5の作⽤  [Not invited]
    倉橋翔太郎、西山伊代、南野莉那、木野貴博、高島康宏、笠波嘉⼈、木野志織、西川裕之、石川千浩、岡田卓哉、関口富美子、坪田真帆、豊岡尚樹、川畑 篤史
    第139回日本薬理学会近畿部会  2021/06  名古屋（リモート）
  • 抗精神病薬pimozideの構造展開による新規選択的T型カルシウムチャネル阻害薬の創製：新たな難治性疼痛治療薬の開発に向けて  [Not invited]
    木野貴博、笠波嘉⼈、石川千浩、高島康宏、長南百⾹、岡田卓哉、関口富美子、吉田繁、大久保つや子、豊岡尚樹、川畑篤史
    第139回日本薬理学会近畿部会  2021/06  名古屋（リモート）
  • 内臓痛におけるマクロファージ由来HMGB1の役割と治療標的分子としての可能性  [Invited]
    川畑篤史
    第126回日本解剖学会総会・全国学術集会と第98回日本生理学会大会の合同大会  名古屋（リモート）
  • 女性癌患者におけるパクリタキセル誘発性末梢神経障害の発症・重症化に寄与する因子について  [Not invited]
    平本志於里、淺野肇、吉年正宏、栁江正嗣、宮本朋佳、竹上学、川畑 篤史
    日本薬学会 第142年会  広島（リモート）
  • 新規T型カルシウムチャネル阻害剤の創製研究  [Not invited]
    田中博人、大井勲、廣瀬雅朗、小川亨、遠藤剛、山川富雄、川畑篤史
    日本薬学会 第141年会  広島（リモート）
  • 学部生における一般名と商品名による医薬品認識に及ぼす病院実務実習の影響  [Not invited]
    家田正子、宮本朋佳、細見光一、高田充隆、竹上学、川畑篤史
    日本薬学会 第141年会  広島（リモート）
  • 神経由来ATPはpaclitaxelによるマクロファージからのHMGB1遊離を促進する：化学療法誘発性末梢神経障害における神経－免疫連関媒介物質としてのATPの役割  [Not invited]
    堂本莉紗、釜口力、家村麻衣子、関口富美子、川畑篤史
    第94回日本薬理学会年会  札幌 (ハイフレックス)
  • マウスおいて硫化物の頬皮内投与により誘起される痒みと痛み：Cav3.2 T型カルシウムチャネル遺伝子欠失の影響  [Not invited]
    倉橋翔太郎、西山伊代、南野莉那、西川裕之、関口富美子、坪田真帆、川畑篤史
    第94回日本薬理学会年会  札幌 (ハイフレックス)
  • Repagermanium水解物はsulfideを捕捉することでH2SによるCav3.2チャネル活性上昇と内臓痛および体性痛を抑制する  [Not invited]
    小池寧々、杉本果歩、増田寛志、島田康弘、佐藤克行、中村宜司、山口浩明、田邉元三、丸本真輔、笠波嘉人、関口富美子、大久保つや子、吉田繁、川畑篤史
    第94回日本薬理学会年会  札幌 (ハイフレックス)
  • 坐骨神経損傷マウスから摘出した後根神経節神経細胞の突起伸長促進にはマクロファージ由来HMGB1が関与する  [Not invited]
    関口富美子, 中武ゆい, 坪田真帆、西堀正洋、川畑篤史
    第94回日本薬理学会年会  札幌 (ハイフレックス)
  • トロンビン阻害薬はHMGB1が関与する結腸痛と膀胱痛を増悪させる：内蔵痛制御における内因性トロンボモジュリン／トロンビン系の役割  [Not invited]
    山縣歩夢、松井和樹、坪田真帆、西堀正洋、川畑篤史
    第94回日本薬理学会年会  札幌 (ハイフレックス)
  • 卵巣摘出マウスにおけるパクリタキセル誘発性末梢神経障害およびHMGB1誘起アロディニアの増悪  [Not invited]
    貫戸綾乃、平本志於里、坪田真帆、松永浩明、宮本朋佳、小泉祐一、西堀正洋、川畑篤史
    第94回日本薬理学会年会  札幌 (ハイフレックス)
  • 前立腺癌の去勢抵抗性獲得と生活習慣病の関連性  [Not invited]
    林 友典、宮本朋佳、平田敦士、長井紀章、川畑篤史
    第138回日本薬理学会近畿部会  2020/11  東大阪（リモート）
  • 糖尿病患者において抗凝固薬は末梢神経障害の発症を促進する：後ろ向きコホート臨床研究による基礎研究知見の検証  [Not invited]
    冨田詩織、田中雅幸、打谷和記、村中達也、川畑篤史
    第138回日本薬理学会近畿部会  2020/11  東大阪（リモート）
  • 中分子ヘパリニルフェニルアラニンはRAGEが関与する痛みを抑制する  [Not invited]
    東本紅瑠美、上野山桐子、西川裕之、関口冨美子、坪田真帆、岡田卓哉、豊岡尚樹、川畑篤史
    第138回日本薬理学会近畿部会  2020/11  東大阪（リモート）
  • 新規Cav3.2阻害剤NCP-1117の薬理プロファイル  [Not invited]
    田中博人、小川亨、中村英生、坪田真帆、小松隆男、今井利安、山川富雄、関口富美子、川畑篤史
    第138回日本薬理学会近畿部会  2020/11  東大阪（リモート）
  • 有機ゲルマニウム化合物repagermaniumのH2S/Cav3.2を介した体性痛および内臓痛に対する抑制効果  [Not invited]
    関口富美子、小池寧々、島田康弘、杉本果歩、増田寛志、佐藤克行、中村宜司、山口浩明、田邉元三、丸本真輔、笠波嘉人、坪田真帆、川畑篤史
    第138回日本薬理学会近畿部会  2020/11  東大阪（リモート）
  • オキサリプラチン誘起末梢神経障害におけるHMGB1の役割とトロンボモジュリン/トロンビン系による抑制的制御  [Not invited]
    坪田 真帆、福田 亮太郎、林 佑亮、宮崎 貴也、上田慎、関口富美子、西堀正洋、川畑篤史
    第70回日本薬学会関西支部大会  2020/10  草津（リモート）
  • 前立腺癌の去勢抵抗性獲得と臨床因子の関連性における探査研究  [Not invited]
    林 友典、宮本朋佳、平田敦士、長井紀章、川畑篤史
    第30回日本医療薬学会年会  2020/09  名古屋（リモート）
  • 閉経後の乳がん患者はパクリタキセル誘発性末梢神経障害の発症・重症化リスクが高い  [Not invited]
    宮本朋佳、富士谷昌典、畑中重克、小泉祐一、川畑篤史
    第30回日本医療薬学会年会  2020/09  名古屋（リモート）
  • 糖尿病性末梢神経障害の発現に及ぼす抗凝固薬の影響に関する後ろ向きコホート研究  [Not invited]
    冨田詩織、田中雅之、打谷和記、村中達也、岡崎和一、川畑篤史
    第30回日本医療薬学会年会  2020/09  名古屋（リモート）
  • Schwann cells from neonatal rat sciatic nerves secrete high mobility group box 1 (HMGB1), a pro-inflammatory and pro-nociceptive mediator, in response to paclitaxel  [Not invited]
    Sekiguchi, F., Yamashita, R., Yasui, H., Kawabata, A
    12th FENS Forum of Neuroscience  Glasgow, UK(リモート）
  • Middle molecular weight heparinylphenylalanine selectively blocks RAGE and reduces HMGB1-dependent neuropathic and visceral pain in mice  [Not invited]
    Kawabata, A., Nishikawa, H. Higashimoto, K., Uenoyama, K., Sekiguchi, F., Tsubota1, M., Okada, T., Toyooka, N
    12th FENS Forum of Neuroscience  Glasgow, UK(リモート）
  • RAGE阻害活性を有する中分子ヘパリニルフェニルアラニンはマウスにおけるoxaliplatin誘発性末梢神経障害およびbutyrate誘起結腸痛を抑制する  [Not invited]
    東本久瑠美、上野山桐子、西川裕之、関口富美子、坪田真帆、豊岡尚樹、川畑篤史
    第93回日本薬理学会年会  横浜(リモート）
  • エストロゲン欠乏によるパクリタキセル誘発性末梢神経障害の増悪：HMGB1の関与について  [Not invited]
    貫戸綾乃、平本志於里、坪田真帆、宮本朋佳、小泉祐一、西堀正洋、川畑篤史
    第93回日本薬理学会年会  横浜(リモート）
  • RepagermaniumはH2Sと直接反応することでH2Sにより誘起されるCav3.2 T型カルシウムチャネル活性および痛み感受性の増大を抑制する  [Not invited]
    小池寧々、杉本果歩、増田寛志、島田康弘、佐藤克行、中村宜司、山口浩明、田邉元三、丸本真輔、笠波嘉人、関口富美子、大久保つや子、吉田 繁、川畑篤史
    第93回日本薬理学会年会  横浜(リモート）
  • 硫化水素産生酵素阻害薬はプロテアソーム阻害薬ボルテゾミブ耐性を獲得したヒト多発性骨髄腫KMS-11細胞の生存を抑制する  [Not invited]
    関口富美子、福島志歩、平本志於里、田中宏和、芦田隆司、松村 到、川畑篤史
    第93回日本薬理学会年会  横浜(リモート）
  • 基礎と臨床の双方向性アプローチによる薬理学研究：がん患者における化学療法のリスク因子解析から見えてきたもの  [Not invited]
    川畑篤史
    第93回日本薬理学会年会  横浜(リモート）
  • Neuroimmune crosstalk in neuropathic and visceral pain: HMGB1 and ATP as key mediators  [Not invited]
    Kawabata, A
    第93回日本薬理学会年会  横浜(リモート）
  • 有機ゲルマニウム化合物repagermaniumはH2Sにより誘起されるCav3.2 T型カルシウムチャネル活性上昇とマウスにおけるアロディニアを直接的に阻害する  [Not invited]
    小池寧々; 杉本果歩; 増田寛志; 島田康弘; 佐藤克行; 中村宜司; 山口浩明; 田邉元三; 丸本真輔; 笠波嘉人; 関口富美子; 川畑篤史
    第136回日本薬理学会近畿部会  2019/11  大阪（枚方）
  • パクリタキセル誘発性末梢神経障害のリスク因子解析：卵巣摘出マウスにおけるパクリタキセル誘発性末梢神経障害の増悪：HMGB1の関与について  [Not invited]
    平本志於里; 貫戸綾乃; 宮本朋佳; 坪田真帆; 小泉祐一; 西堀正洋; 川畑篤史
    第136回日本薬理学会近畿部会  2019/11  大阪（枚方）
  • パクリタキセル誘発性末梢神経障害のリスク因子解析：がんの種類による違いと加齢の影響について  [Not invited]
    宮本朋佳; 平本志於里; 貫戸綾乃; 富士谷昌典; 畑中重克; 坪田真帆; 小泉祐一; 川畑篤史
    第136回日本薬理学会近畿部会  2019/11  大阪（枚方）
  • ヒト多発性骨髄腫由来KMS-11細胞のボルテゾミブ耐性獲得における内因性硫化水素の役割  [Not invited]
    福島志歩; 平本志於里; 関口富美子; 田中宏和; 芦田隆司; 松村 到; 川畑篤史
    第69回日本薬学会関西支部総会・大会  2019/10  神戸
  • 生体内においてトロンビン・トロンボモジュリン系は内臓痛を抑制的に制御している  [Not invited]
    山縣歩夢; 松井和樹; 坪田真帆; 川畑篤史
    第69回日本薬学会関西支部総会・大会  2019/10  神戸
  • 肝障害によるオキサリプラチン誘発性末梢神経障害の増悪： 病原因子HMGB1を遊離する肝内細胞の探索  [Not invited]
    釜口 力; 堂本莉紗; 西村莉香; 関口富美子; 坪田真帆; 西堀正洋; 川畑篤史
    第69回日本薬学会関西支部総会・大会  2019/10  神戸
  • 中分子ヘパリニルフェニルアラニンのRAGE阻害活性とマウスにおけるoxaliplatin誘発性末梢神経障害およびbutyrate誘起結腸痛に対する抑制作用  [Not invited]
    東本紅瑠美; 上野山桐子; 西川裕之; 関口富美子; 坪田真帆; 岡田卓哉; 豊岡尚樹; 川畑篤史
    第69回日本薬学会関西支部総会・大会  2019/10  神戸
  • Role of T-type calcium channels in methamphetamine-induced hyperlocomotion and neuronal excitation in mice.  [Not invited]
    Koike, N; Yasui, H; Sekiguchi, F; Tanabe, G; Kawabata, A
    The 6th Asian College of Neuropsychopharmacology (AsCNP) Congress  2019/10  福岡
  • Involvement of HMGB1 in bortezomib-induced peripheral neuropathy in mice.  [Not invited]
    Ikeda, Y; Miyazak, T; Tsubota, M; Tomita, S; Sekiguchi, F; Nishibori, M; Kawabata, A
    The 6th Asian College of Neuropsychopharmacology (AsCNP) Congress  2019/10  福岡
  • Endogenous thrombin plays a preventive role against oxaliplatin-induced peripheral neuropathy: involvement of thrombomodulin-dependent inactivation of HMGB1 by thrombin.  [Not invited]
    Tsubota, M; Fukuda, R; Hayashi, Y; Miyazaki, T; Ueda, S; Nishibori, M; Kawabata, A
    The 6th Asian College of Neuropsychopharmacology (AsCNP) Congress  2019/10  福岡
  • Paclitaxel, an anti-cancer drug, causes extracellular release of HMGB1, a pro-inflammatory and pro-nociceptive mediator, in Schwann cells derived from neonatal rat sciatic nerves.  [Not invited]
    Sekiguchi, F; Yamashita, R; Yasui, H; Kawabata, A
    The 6th Asian College of Neuropsychopharmacology (AsCNP) Congress  2019/10  福岡
  • Role of HMGB1 and PRRs in pain processing.  [Not invited]
    Kawabata, A
    The 6th Asian College of Neuropsychopharmacology (AsCNP) Congress  2019/10  福岡
  • Crosstalk between the HMGB1/RAGE and CSE/H2S/Cav3.2 pathways involved in cystitis-related bladder pain in mice.  [Not invited]
    Hiramoto, S; Tsubota, M; Yamaguchi, K; Okazaki, K; Tanaka, J; Sekiguchi, F; Ishikura, H; Nishibori, M; Kawabata, A
    11th Congress of the European Pain Federation EFIC (2019 Pain in Europe XI),  2019/09  Valencia, Spain
  • Hepatic injury aggravates oxaliplatin-induced peripheral neuropathy in mice: possible involvement of HMGB1.  [Not invited]
    Domoto, R; Fukuda, R; Sekiguchi, F; Tsubota, M; Nishibori, M; Kawabata, A
    11th Congress of the European Pain Federation EFIC (2019 Pain in Europe XI),  2019/09  Valencia, Spain
  • Critical role of Cav3.2 T-type calcium channels in H2S-dependent somatic and visceral pain signaling in mice.  [Not invited]
    Matsui, K; Fukushi, S; Koike, N; Yamagata, A; Tsubota, M; Mukai, Y; Oita, A; Takada, M; Kawabata, A
    11th Congress of the European Pain Federation EFIC (2019 Pain in Europe XI),  2019/09  Valencia, Spain
  • 6-Prenylnaringenin and its derivative, KTt45, are mixed T-type Ca2+ channel inhibitors/CB2 receptor agonists: antinociceptive activity in neuropathic and visceral pain models.  [Not invited]
    Sekiguchi, F; Kasanami, Y; Onishi, R; Tsubota, M; Miyazaki, T; Hiramoto, S; Okazaki, K; Nguyen, H.D; Okada, T; Toyooka, N; Yoshida, S; Ohkubo, T; Kawabata, A
    11th Congress of the European Pain Federation EFIC (2019 Pain in Europe XI),  2019/09  Valencia, Spain
  • Dietary ascorbic acid restriction in GNL/SMP30-knockout mice unveils the role of ascorbic acid in regulation of Cav3.2-dependent pain.  [Not invited]
    Kawabata, A; Tsubota, M; Uebo, K; Miki, K; Sekiguchi, F; Ishigami, A
    11th Congress of the European Pain Federation EFIC (2019 Pain in Europe XI),  2019/09  Valencia, Spain
  • 有機ゲルマニウム化合物repagermanium水解物は気体メディエーターH2Sを捕捉することでアロディニアを抑制する．  [Not invited]
    小池寧々; 杉本果歩; 島田康弘; 佐藤克行; 中村宣司; 山口浩明; 田邉元三; 関口富美子; 川畑篤史
    次世代を担う創薬・医療薬理シンポジウム  2019/08  東京
  • オキサリプラチン誘起末梢神経障害におけるHMGB1系とトロンボモジュリン/トロンビン系の相反的役割．  [Not invited]
    坪田真帆; 福田亮太郎; 林 佑亮; 宮崎貴也; 上田 慎; 関口富美子; 西堀正洋; 川畑篤史
    次世代を担う創薬・医療薬理シンポジウム  2019/08  東京
  • エストロゲンはパクリタキセル誘発性末梢神経障害に対して抑制的に作用する：マクロファージ由来HMGB1との関係について．  [Not invited]
    貫戸綾乃; 平本志於里; 宮本朋佳; 坪田真帆; 小泉祐一; 西堀正洋; 川畑篤史
    生体機能と創薬シンポジウム2019  2019/08  東京
  • Repagermanium水解物3-(trihydroxygermyl)propanoic acid (THGP)はH2Sに直接作用し外因性および内因性H2Sによるアロディニアを抑制する．  [Not invited]
    杉本果歩; 小池寧々; 島田康弘; 佐藤克行; 中村宜司; 山口浩明; 田邉元三; 関口富美子; 川畑篤史
    生体機能と創薬シンポジウム2019  2019/08  東京
  • 覚醒剤メタンフェタミンにより誘起されるマウスの行動量増加と脳内cFos発現におけるT型カルシウムチャネルの役割．  [Not invited]
    小池寧々; 安井洋樹; 関口富美子; 田邉元三; 川畑篤史
    生体機能と創薬シンポジウム2019  2019/08  東京
  • 化学療法誘発性末梢神経障害のリスク因子解析とHMGB1を標的とする予防戦略：基礎研究と臨床研究の融合による新知見とイノベーション．  [Not invited]
    川畑篤史
    生体機能と創薬シンポジウム2019  2019/08  東京
  • Role of peripheral HMGB1 and thrombomodulin/thrombin in neuropathic pain.  [Not invited]
    Kawabata, A
    第42回日本神経科学会  2019/07  新潟
  • マウスにおけるbortezomib誘発性末梢神経障害の発症および維持におけるHMGB1の役割とその起源．  [Not invited]
    池田裕哉; 宮崎貴也; 坪田真帆; 冨田詩織; 関口富美子; 西堀正洋; 川畑篤史
    第135回日本薬理学会近畿部会  2019/06  岐阜
  • マウスにおいて肝障害により放出されるHMGB1はボルテゾミブ誘発性末梢神経障害を増悪させる．  [Not invited]
    堂本莉紗; 宮本朋佳; 関口富美子; 坪田真帆; 小泉祐一; 西堀正洋; 川畑篤史
    第135回日本薬理学会近畿部会  2019/06  岐阜
  • 肝障害はボルテゾミブ誘発性末梢神経障害の発症リスクを増大させる．  [Not invited]
    宮本朋佳; 富士谷昌典; 堂本莉紗; 畑中重克; 福山紘基; 関口富美子; 小泉祐一; 川畑篤史
    第135回日本薬理学会近畿部会  2019/06  岐阜
  • Distinct effects of T-type Ca2+ channel blockers and genetic deletion of Cav3.2 on somatic and visceral hypersensitivity.  [Not invited]
    Kawabata, A
    International Calcium Channel Meeting 2019  2019/03  大阪
  • マウスにおけるbortezomib誘発性末梢神経障害に関与するHMGB1の起源と標的分子：発症期と維持期における違いについて．  [Not invited]
    池田裕哉; 宮崎貴也; 坪田真帆; 冨田詩織; 関口富美子; 西堀正洋; 川畑篤史
    第92回日本薬理学会年会  2019/03  大阪
  • T型カルシウムチャネルはマウスにおいてメタンフェタミンにより誘起される行動量増加および脳内特定部位におけるcFos発現に関与する．  [Not invited]
    小池寧々; 安井洋樹; 関口富美子; 田邉元三; 川畑篤史
    第92回日本薬理学会年会  2019/03  大阪
  • PaclitaxelによるマクロファージからのHMGB1遊離におけるcystathionine γ-lyase/H2S系の役割と末梢神経障害への関与  [Not invited]
    山口一樹; 堂本莉紗; 関口富美子; 坪田真帆; 川畑篤史
    第92回日本薬理学会年会  2019/03  大阪
  • T型カルシウムチャネル、カンナビノイド受容体および難治性疼痛に及ぼすホップ成分6-prenylnaringeninとその誘導体KTt45の効果．  [Not invited]
    笠波嘉人; 大西伶佳; 木野貴博; 関口富美子; 坪田真帆; 宮崎貴也; 平本志於里; 岡崎杏子; Nguyen Huy Du; 岡田卓哉; 豊岡尚樹; 吉田 繁; 大久保つや子; 川畑篤史
    第92回日本薬理学会年会  2019/03  大阪
  • マウスにおいて膀胱炎に伴う疼痛シグナル発生に関与するHMGB1/RAGE系とCSE/H2S/Cav3.2系のクロストーク：ATPによるマクロファージ活性化の役割．  [Not invited]
    平本志於里; 鳥山祐希; 榮木彩; 山口薫; 坪田真帆; 田中潤一; 関口富美子; 石倉宏恭; 西堀正洋; 川畑篤史
    第92回日本薬理学会年会  2019/03  大阪
  • ヒトおよびマウスにおいて肝障害はオキサリプラチン誘発性末梢神経障害の増悪因子である：HMGB1が関与する可能性について．  [Not invited]
    堂本莉紗; 宮本朋佳; 西村莉香; 福田亮太郎; 関口富美子; 坪田真帆; 小泉祐一; 西堀正洋; 川畑篤史
    第92回日本薬理学会年会  2019/03  大阪
  • 硫化水素によるCav3.2を介する疼痛シグナルの調節．  [Not invited]
    坪田真帆; 川畑篤史
    第92回日本薬理学会年会  2019/03  大阪
  • 前立腺がん細胞における低電位活性化Cav3.2 T型カルシウムチャネルの役割．  [Not invited]
    関口富美子; 川畑篤史
    第92回日本薬理学会年会  2019/03  大阪
  • HMGB1を標的とする化学療法誘発性末梢神経障害の発症予防．  [Not invited]
    川畑篤史
    第92回日本薬理学会年会  2019/03  大阪
  • マクロファージにおいてパクリタキセルにより誘発される内因性H2Sに依存したHMGB1遊離：化学療法誘発性末梢神経障害への関与  [Not invited]
    堂本莉紗; 山口一樹; 関口富美子; 坪田真帆; 川畑篤史
    痛み研究会2018  2018/12  岡崎
  • 化学療法誘発性末梢神経障害の原因物質としてのHMGB1の役割：臨床データ解析と基礎研究を駆使したアプローチ．  [Not invited]
    川畑篤史
    痛み研究会2018  2018/12  岡崎
  • マウスにおいて覚醒剤メタンフェタミンにより誘起される行動量増加と脳内cFos発現に及ぼすT型カルシウムチャネル阻害薬の効果  [Not invited]
    小池寧々; 安井洋樹; 関口富美子; 田邉元三; 川畑篤史
    第134回日本薬理学会近畿部会  2018/11  神戸
  • トロンボモジュリン／トロンビン系はHMGB1を不活性化することでオキサリプラチン誘発性末梢神経障害の発症を抑制的に制御している．  [Not invited]
    林 佑亮; 坪田真帆; 福田亮太郎; 宮崎貴也; 西堀正洋; 川畑篤史
    第134回日本薬理学会近畿部会  2018/11  神戸
  • マウスにおいてオキサリプラチン誘発性末梢神経障害は肝障害によって増悪する．  [Not invited]
    堂本莉紗; 西村莉香; 関口富美子; 坪田真帆; 宮本朋佳; 小泉祐一; 西堀正洋; 川畑篤史
    第134回日本薬理学会近畿部会  2018/11  神戸
  • オキサリプラチン誘発末梢神経障害のリスク因子：肝機能障害との関係について．  [Not invited]
    宮本朋佳; 福山紘基; 畑中重克; 富士谷昌典; 堂本莉紗; 関口富美子; 小泉祐一; 川畑篤史
    第134回日本薬理学会近畿部会  2018/11  神戸
  • Cav3.2 T型カルシウムチャネル − どこで何をしているのか？  [Not invited]
    川畑篤史
    第134回日本薬理学会近畿部会  2018/11  神戸
  • 内臓痛発現における硫化水素および過硫化物の役割．  [Not invited]
    坪田真帆; 川畑篤史
    第91回日本生化学会大会  2018/09  京都
  • Azelastine attenuates RAGE-dependent allodynia in mice: a discovery by a drug reprofiling/repositioning approach.  [Not invited]
    Wakitani, K; Sekiguchi, F; Tsubota, M; Nakamura, S; Nakanishi, I; Kawabata, A
    17th World Congress on Pain.  2018/09  Boston, USA
  • Pharmacological blockade and genetic deletion of Cav3.2 T-type Ca2+ channels abolish butyrate-induced colonic hypersensitivity in mice.  [Not invited]
    Matsui, K; Nakano, M; Tomochika, K; Tsubota, M; Kawabata, A
    17th World Congress on Pain.  2018/09  Boston, USA
  • Middle Molecular Weight Heparinylphenylalanine Prevents the Development of Chemotherapy-Induced Peripheral Neuropathy in Mice.  [Not invited]
    Kawabata, A; Nishikawa, H; Uenoyama, K; Sekiguchi, F; Tsubota, M; Okada, T; Toyooka, N
    17th World Congress on Pain.  2018/09  Boston, USA
  • DAMPsと痛み．  [Not invited]
    川畑篤史
    第40回日本生物学的精神医学会・第61回日本神経化学大会合同年会  2018/09  神戸
  • オキサリプラチン誘起末梢神経障害に対するトロンボモジュリンアルファの予防効果に及ぼす抗凝固薬の影響．  [Not invited]
    林 佑亮; 坪田真帆; 福田亮太郎; 宮崎貴也; 西堀正洋; 川畑篤史
    生体機能と創薬シンポジウム2018  2018/08  福岡
  • Cyclophosphamide誘起膀胱炎マウスにおいてATP/HMGB1/RAGE系はCSE/H2S/Cav3.2系の上流シグナルとして膀胱痛の発症に関与する  [Not invited]
    平本志於里; 鳥山祐希; 榮木?彩; 坪田真帆; 山口 薫; 田中潤一; 関口富美子; 石倉宏恭; 西堀正洋; 川畑篤史
    生体機能と創薬シンポジウム2018  2018/08  福岡
  • PaclitaxelによるマクロファージからのHMGB1放出はニューロン由来ATPによって促進される：化学療法誘起末梢神経障害における神経系−免疫系クロストークの役割  [Not invited]
    堂本莉紗; 関口富美子; 坪田真帆; 西堀正洋; 川畑篤史
    生体機能と創薬シンポジウム2018  2018/08  福岡
  • Effect of extracellular HMGB1 on neuritogenesis in mouse dorsal root ganglion neurons and its inhibition by thrombomodulin alfa.  [Not invited]
    Nakatake, Y; Sekiguchi, F; Tsubota, M; Tsujita, R; Honda, G; Kawabata, A
    11thFENS Forum of Neuroscience.  2018/07  Berlin, Germany
  • ATP and HMGB1 mediate H2S-dependent bladder pain in mice with cyclophosphamide-induced cystitis.  [Not invited]
    Hiramoto, S; Tsubota, M; Yamaguchi, K; Toriyama, Y; Tanaka, J; Sekiguchi, F; Ishikura, H; Nishibori, M; Kawabata, A
    11thFENS Forum of Neuroscience.  2018/07  Berlin, Germany
  • Molecular mechanisms for the HMGB1-dependent mechanical allodynia following intraplantar administration of lipopolysaccharidein mice.  [Not invited]
    Domoto, R; Yamasoba, D; Sekiguchi, F; Tsubota, M; Nishibori, M; Kawabata, A
    11thFENS Forum of Neuroscience.  2018/07  Berlin, Germany
  • A. Agonistic activity of 6-prenylnaringenin, a novel T-type Ca2+ channel inhibitor, toward cannabinoid CB1 receptors in neural progenitor-like NG108-15 cells and CB1-transfected HEK293 cells.  [Not invited]
    Sekiguchi, F; Noda, S; Kasanami, Y; Onishi, R; Ono, S; Murata, K; Matsuda, H; Nguyen, H.D; Toyooka, N; Harada, N; Kawabata, A
    11thFENS Forum of Neuroscience.  2018/07  Berlin, Germany
  • Cav3.2 T-type calcium channels as therapeutic targets for bortezomib-induced peripheral neuropathy in mice.  [Not invited]
    Kawabata, A; Tomita, S; Miyazaki, T; Deguchi, T; Sekiguchi, F; Tsubota, M; Nguyen, H.D; Okada, T; Yoshida, S; Toyooka, N
    11thFENS Forum of Neuroscience.  2018/07  Berlin, Germany
  • Molecular mechanisms for the recombinant soluble thrombomodulin-induced suppression of HMGB1-dependent allodynia in mice: Roles of the N-terminal domains of thrombomodulin.  [Not invited]
    Hayashi, Y; Tsubota, M; Tsujita, R; Honda, G; Kawabata, A
    18th World Congress of Basic and Clinical Pharmacology  2018/07  Kyoto, Japan
  • Macrophage-derived HMGB1 is a key molecule in paclitaxel-induced peripheral neuropathy in mice: involvement of ROS generation and NF-κB activation.  [Not invited]
    Domoto, R; Yamasoba, D; Yamanishi, H; Sekiguchi, F; Tsubota, M; Nishibori, M; Kawabata, A
    18th World Congress of Basic and Clinical Pharmacology  2018/07  Kyoto, Japan
  • Middle molecular weight heparinylphenylalanine is an analgesic with reduced risk of hemorrhage.  [Not invited]
    Nishikawa, H; Uenoyama, K; Sekiguchi, F; Tsubota, M; Kawabata, A
    18th World Congress of Basic and Clinical Pharmacology  2018/07  Kyoto, Japan
  • High mobility group box 1 suppresses smooth muscle tension in rat aorta via Toll-like receptor 4-dependent upregulation of iNOS.  [Not invited]
    Sekiguchi, F; Yagura, A; Kawabata, A
    18th World Congress of Basic and Clinical Pharmacology  2018/07  Kyoto, Japan
  • Role of Cav3.2 T-type calcium channels in the butyrate-induced colonic hypersensitivity in the mouse, a model for irritable bowel syndrome  [Not invited]
    Tsubota, M; Matsui, K; Nakano; M. Tomochika, K; Sekiguchi, F; Kawabata, A
    10th International Symposium on Cell/Tissue Injury and Cytoprotection/Organoprotection.  2018/06  Kyoto, Japan
  • RAGEを標的とした化学療法誘起末梢神経障害治療薬の探索： In silicoドラッグ・リプロファイリング/リポジショニングからのアプローチ  [Not invited]
    脇谷航平; 関口富美子; 坪田真帆; 中村真也; 仲西功; 川畑篤史
    第40回日本疼痛学会  2018/06  長崎
  • 急性および慢性術後痛におけるHMGB1の役割  [Not invited]
    川端柚希; 林愛理沙; 坪田真帆; 中武ゆい; 辻田隆一; 関口富美子; 西堀正洋; 川畑篤史
    第40回日本疼痛学会  2018/06  長崎
  • 中分子ヘパリニルフェニルアラニンは化学療法誘起末梢神経障害を抑制する  [Not invited]
    西川裕之; 上野山桐子; 関口富美子; 坪田真帆; 岡田卓哉; 豊岡尚樹; 川畑篤史
    第40回日本疼痛学会  2018/06  長崎
  • 内臓痛におけるマクロファージ由来 HMGB1の役割と治療標的分子としての可能性  [Not invited]
    川畑篤史
    第40回日本疼痛学会  2018/06  長崎
  • AzelastineはRAGEが関与する化学療法誘起末梢神経障害の発症を抑制する − ドラッグ・リプロファイリング／リポジショニング研究からの知見  [Not invited]
    脇谷航平; 関口富美子; 坪田真帆; 中村真也; 仲西功; 川畑篤史
    第133回日本薬理学会近畿部会  2018/06  広島
  • T型Ca2+チャネル阻害活性を有するホップ成分6-prenylnaringeninは結腸痛を抑制する  [Not invited]
    坪田真帆; 松井和樹; 中野真希; 友近拳; 関口富美子; 川畑篤史
    第133回日本薬理学会近畿部会  2018/06  広島
  • がん化学療法誘起末梢神経障害モデルマウスにおける中分子ヘパリニルフェニルアラニンの抗アロディニア作用  [Not invited]
    西川裕之; 上野山桐子; 関口富美子; 坪田真帆; 岡田卓哉; 豊岡尚樹; 川畑篤史
    第133回日本薬理学会近畿部会  2018/06  広島
  • 慢性疼痛におけるCav3.2 T型カルシウムチャネルの役割と治療標的分子としての可能性  [Not invited]
    川畑篤史
    第61回日本糖尿病学会年次学術集会  2018/05  東京
  • HMGB1 による痛みの増強に対するヒト型可溶性トロンボモジュリンの抑制作用に関与する分子メカニズム  [Not invited]
    辻田隆一; 坪田真帆; 林佑亮; 佐伯晴香; 本田剛一; 川畑篤史
    第40回日本神経科学大会  2017/12  名古屋
  • T型カルシウムチャネルを標的とする難治性疼痛の治療．ワークショップ「カルシウムシグナル動態制御の分子基盤と疾患治療戦略  [Not invited]
    川畑篤史
    2017年度生命科学系学会合同年次大会（ConBio2017）  2017/12  神戸
  • 新規T型Ca2+チャネル阻害薬6-prenylnaringeninとその誘導体はカンナビノイドCB1受容体を介して神経前駆NG108-15細胞の神経様突起伸長を誘起する  [Not invited]
    関口富美子; 野田紗友理; 洞口大和; 山岡 桜; 笠波嘉人; 大野 菫; Nguyen Huy Du; 豊岡尚樹; 村田和也; 松田秀秋; 吉田 繁; 原田成信; 伊藤由香里; 大久保つや子; 川畑篤史
    第132回日本薬理学会近畿部会  2017/11  豊中
  • Cyclophosphamide誘起膀胱炎マウスにおけるH2S/Cav3.2系を介する膀胱痛の発現：NF-κB系の役割と亜鉛による制御  [Not invited]
    尾崎友香; 松岡順紀; 坪田真帆; 冨田詩織; 関口富美子; 南武志; 川畑篤史
    第132回日本薬理学会近畿部会  2017/11  豊中
  • Butyrate誘起過敏性腸症候群モデルマウスの知覚神経過敏におけるCav3.2 T型Ca2+チャネルの役割  [Not invited]
    坪田真帆; 川畑篤史
    第45回日本潰瘍学会  2017/11  京都
  • Involvement of HMGB1 in postoperative pain.  [Not invited]
    Kawabata, Y; Tsubota, M; Tsujita, R; Nishibori, M; Kawabata, A
    Neuroscience 2017  2017/11  Washington DC, USA
  • Thrombin-dependent inhibition of HMGB1-induced mechanical allodynia by thrombomodulin in mice.  [Not invited]
    Hayashi, Y; Tsubota, M; Tsujita, R; Honda, G; Kawabata, A
    Neuroscience 2017  2017/11  Washington DC, USA
  • HMGB1-induced neurite outgrowth in mouse dorsal root ganglion neurons and its inhibition by thrombomodulin  [Not invited]
    Nakatake, Y; Sekiguchi, F; Tsubota, M; Tsujita, R; Honda, G; Kawabata, A
    Neuroscience 2017  2017/11  Washington DC, USA
  • Macrophages and NF-κB signaling mediate peripheral HMGB1-induced mechanical allodynia in mice.  [Not invited]
    Domoto, R; Nakashima, K; Tsubota, M; Sekiguchi, F; Kawabata, A
    Neuroscience 2017  2017/11  Washington DC, USA
  • Tacrolimus, a calcineurin inhibitor, promotes capsaicin-induced colonic pain in mice  [Not invited]
    Matsui, K; Terada, Y; Tsubota, M; Kawabata, A
    Neuroscience 2017  2017/11  Washington DC, USA
  • Involvement of Cav3.2 T-type calcium channels in zinc deficiency-induced mechanical allodynia in mice.  [Not invited]
    Sekiguchi, F; Tomita, S; Shikimi, S; Tsubota, M; Kawabata, A
    Neuroscience 2017  2017/11  Washington DC, USA
  • The critical role of Cav3.2 T-type calcium channels in the peripheral neuropathy induced by bortezomib, a proteasome-inhibiting chemotherapy agent, in mice.  [Not invited]
    Kawabata, A; Tomita, S; Deguchi, T; Sekiguchi, F; Tsubota, M; Yoshida, S
    Neuroscience 2017  2017/11  Washington DC, USA
  • 核内タンパクhigh mobility group box 1はラット胸部大動脈においてiNOS発現誘導を促進することでフェニレフリン収縮を抑制する．  [Not invited]
    矢倉綾乃; 関口富美子; 川畑篤史
    第67回日本薬学会近畿支部大会  2017/10  神戸
  • Cyclophosphamide誘起膀胱炎マウスにおける亜鉛欠乏による膀胱痛増強メカニズム ―Cav3.2 T型Ca2+チャネルの機能増強と発現増加の関与―  [Not invited]
    尾崎友香; 松岡順紀; 坪田真帆; 冨田詩織; 関口富美子; 南武志; 川畑篤史
    第67回日本薬学会近畿支部大会  2017/10  神戸
  • プロテアソーム阻害作用を有する多発性骨髄腫治療薬bortezomibによって誘起されるマウスの神経障害性疼痛には一次知覚神経におけるCav3.2 T型Ca2+チャネルの発現量増加が関与する．  [Not invited]
    関口富美子; 冨田詩織; 出口智代; 坪田真帆; 吉田繁; 川畑篤史
    第39回日本生物学的精神医学会・第47回日本神経精神薬理学会 合同年会  2017/09  札幌
  • Bortezomib誘起神経障害性疼痛へのマクロファージ由来HMGB1の関与  [Not invited]
    宮崎貴也; 坪田真帆; 冨田詩織; 出口智代; 関口富美子; 西堀正洋; 川畑篤史
    次世代を担う創薬・医療薬理シンポジウム2017  2017/08  京都
  • マウスにおいてHMGB1足底内投与により誘起される機械的アロディニアにはNF-κBシグナルとマクロファージが関与する  [Not invited]
    堂本 莉紗; 中島夏奈; 関口富美子; 坪田真帆; 川畑篤史
    次世代を担う創薬・医療薬理シンポジウム2017  2017/08  京都
  • Butyrate誘起過敏性腸症候群モデルマウスにおける結腸痛へのマクロファージ由来HMGB1の関与  [Not invited]
    坪田真帆; 梶谷梨絵; 野中結; 石井優子; 関口富美子; 西堀正洋; 川畑篤史
    次世代を担う創薬・医療薬理シンポジウム2017  2017/08  京都
  • Butyrate誘起過敏性腸症候群モデルマウスにおける結腸の知覚神経過敏におけるCav3.2 T型Ca2+チャネルの役割．  [Not invited]
    松井和樹; 中野真希; 友近拳; 坪田真帆; 川畑篤史
    生体機能と創薬シンポジウム2017  2017/08  京都
  • 術後痛におけるHMGB1シグナルの役割と治療標的分子としての可能性．  [Not invited]
    川端柚希; 坪田真帆; 辻田隆一; 西堀正洋; 川畑篤史
    生体機能と創薬シンポジウム2017  2017/08  京都
  • レドックス状態の異なるHMGB1による機械的アロディニアの発現メカニズムの解析：Toll-like receptor 5、NMDA受容体およびNF-κBの関与とマクロファージの役割．  [Not invited]
    中島夏奈; 堂本莉紗; 関口富美子; 坪田真帆; 川畑篤史
    生体機能と創薬シンポジウム2017  2017/08  京都
  • マウス後根神経節細胞においてthrombomodulin alfaは還元型HMGB1により誘起される神経突起伸長をトロンビン依存的および非依存的に抑制する．  [Not invited]
    中武ゆい; 関口富美子; 坪田真帆; 辻田隆一; 本田剛一; 川畑篤史
    生体機能と創薬シンポジウム2017  2017/08  京都
  • トロンボモジュリンアルファはトロンビン依存的にHMGB1を分解し炎症性疼痛を抑制する．  [Not invited]
    林 佑亮; 佐伯晴香; 坪田真帆; 辻田隆一; 本田剛一; 川畑篤史
    生体機能と創薬シンポジウム2017  2017/08  京都
  • HMGB1 and pain.  [Not invited]
    Kawabata, A
    第40回日本神経科学大会  2017/07  千葉
  • Cav3.2 T型カルシウムチャネルを標的とするオキサリプラチン誘起末梢神経障害の治療  [Not invited]
    坪田 真帆; 福田 亮太郎; 宮崎 貴也; 川畑 篤史
    第40回日本神経科学大会  2017/07  千葉
  • 6-prenylnaringeninは神経前駆様NG108-15細胞においてT型カルシウムチャネル阻害活性とカンナビノイドCB1受容体アゴニスト活性を示す．  [Not invited]
    関口富美子; 野田紗友理; 大野 菫; 洞口大和; 笠波嘉人; Nguyen Huy Du; 豊岡尚樹; 村田和也; 松田秀秋; 原田成信; 伊藤由香里; 川畑篤史
    第40回日本神経科学大会  2017/07  千葉
  • マウス脊髄後根神経節細胞におけるHMGB1誘起神経突起伸長とそれに対する遺伝子組み換えヒト可溶性thrombomodulinの効果  [Not invited]
    中武ゆい; 関口富美子; 坪田真帆; 辻田隆一; 本田剛一; 川畑篤史
    第131回日本薬理学会近畿部会  2017/06  名古屋
  • 末梢組織中のチオール型およびジスルフィド型high mobility group box 1により誘起される痛覚増強へのマクロファージの関与．  [Not invited]
    中島夏奈; 堂本莉紗; 関口富美子; 坪田真帆; 川畑篤史
    2017/06  名古屋
  • マクロファージ由来high mobility group box1はbortezomib誘起神経障害性疼痛に関与する．  [Not invited]
    宮崎貴也; 坪田真帆; 冨田詩織; 出口智代; 関口富美子; 西堀正洋; 川畑篤史
    2017/06  名古屋
  • トロンボモジュリンアルファはトロンビン依存性にHMGB1誘起痛覚過敏を抑制する  [Not invited]
    辻田隆一; 林佑亮; 坪田真帆; 本田剛一; 川畑篤史
    第39回日本疼痛学会  2017/06  神戸
  • プロテアソーム阻害薬bortezomib誘起神経障害性疼痛には一次知覚神経におけるCav3.2 T型カルシウムチャネルのタンパク量増加が関与する．  [Not invited]
    関口富美子; 冨田詩織; 出口智代; 坪田真帆; 吉田繁; 川畑篤史
    第39回日本疼痛学会  2017/06  神戸
  • シクロホスファミド誘起間質性膀胱炎様マウスモデルにおける膀胱痛はATP/HMGB1/H2Sシグナルを介して発現する．  [Not invited]
    平本 志於里; 山口薫; 坪田真帆; 田中潤一; 関口富美子; 石倉宏恭; 西堀正洋; 川畑篤史
    第39回日本疼痛学会  2017/06  神戸
  • オキサリプラチン誘起神経障害性疼痛の発症メカニズムの解析：Cav3.2 T型カルシウムチャネルとHMGB1の関与．  [Not invited]
    坪田真帆; 福田亮太郎; 関口富美子; 宮崎貴也; 堂本莉紗; 安井洋樹; 山下莉加; 上田慎; 西田武司; 石倉宏恭; 西堀正洋; 川畑篤史
    第39回日本疼痛学会  2017/06  神戸
  • パクリタキセルによるマクロファージからのHMGB1遊離の分子メカニズム：化学療法誘起末梢神経障害の発症における役割．  [Not invited]
    第90回日本薬理学会年会  2017/03  長崎
  • マウスにおけるシクロホスファミド誘起膀胱炎・膀胱痛は反復寒冷ストレスにより軽減される：ストレスによるマクロファージ機能低下の関与について．  [Not invited]
    宮本朋佳; 坪田真帆; 昼馬佐紀; 川畑篤史
    第90回日本薬理学会年会  2017/03  長崎
  • 結腸痛発症メカニズムの解析：侵害受容ニューロン発現分子TRPV1、PAR2およびCav3.2の役割．  [Not invited]
    松井和樹; 中野真希; 石井優子; 寺田侑加; 坪田真帆; 川畑篤史
    第90回日本薬理学会年会  2017/03  長崎
  • トロンボモジュリンアルファのHMGB1誘起痛覚過敏に対する抑制効果はトロンビンに依存する．  [Not invited]
    林佑亮; 坪田真帆; 辻田隆一; 本田剛一; 川畑篤史
    第90回日本薬理学会年会  2017/03  長崎
  • HMGB1は術後痛に関与する．  [Not invited]
    川端柚希; 坪田真帆; 辻田隆一; 西堀正洋; 川畑篤史
    第90回日本薬理学会年会  2017/03  長崎
  • がん薬ボルテゾミブにより誘起される神経障害性疼痛にはCav3.2 T型カルシムチャネルの発現増加が関与する．  [Not invited]
    冨田詩織; 出口智代; 関口富美子; 坪田真帆; 川畑篤史
    第90回日本薬理学会年会  2017/03  長崎
  • Oxaliplatin誘起神経障害性疼痛におけるHMGB1とその標的分子の役割：マクロファージ非依存的機序の関与について  [Not invited]
    坪田真帆; 福田亮太郎; 関口富美子; 宮崎貴也; 堂本莉紗; 安井洋樹; 西田武司; 石倉宏恭; 西堀正洋; 川畑篤史
    第90回日本薬理学会年会  2017/03  長崎
  • Paclitaxel誘起痛覚過敏へのマクロファージ由来high mobility group box 1の関与  [Not invited]
    堂本莉紗; 山岨大智; 山西広樹; 関口富美子; 坪田真帆; 西堀正洋; 川畑篤史
    み研究会2016「痛みの理解を目指した先端的アプローチ」  2017/01  岡崎
  • 抗がん薬オキサリプラチン誘起神経障害性疼痛へのCav3.2 T型Ca2+チャネルとHMGB1の関与について．  [Not invited]
    坪田真帆; 福田亮太郎; 関口富美子; 宮崎貴也; 堂本莉紗; 安井洋樹; 山下莉加; 西田武司; 石倉宏恭; 西堀正洋; 川畑篤史
    2017/01  岡崎
  • トロンボモジュリンアルファのHMGB1誘起痛覚過敏に対する抑制作用の分子メカニズムとトロンビン依存性の解析．  [Not invited]
    林佑亮; 坪田真帆; 辻田隆一; 本田剛一; 川畑篤史
    第130回日本薬理学会近畿部会  2016/11  京都
  • シクロホスファミド誘起膀胱痛の発現メカニズムの解析：マクロファージ由来HMGB1によるRAGE活性化を介するH2S産生酵素の発現誘導の関与．  [Not invited]
    平本志於里; 山口薫; 坪田真帆; 田中潤一; 関口富美子; 石倉宏恭; 西堀正洋; 川畑篤史
    第130回日本薬理学会近畿部会  2016/11  京都
  • ヒト前立腺癌細胞におけるinterleukin-6誘起神経内分泌様分化に伴うCav3.2 T型カルシウムチャネルの発現増加に関与する細胞シグナルの解析．  [Not invited]
    上田舞; 深海和樹; 浅野絵莉茄; 関口富美子; 吉田繁; 川畑篤史
    第130回日本薬理学会近畿部会  2016/11  京都
  • Bortezomib誘起神経障害性疼痛への核内タンパクhigh mobility group box1の関与．  [Not invited]
    宮崎貴也; 坪田真帆; 冨田詩織; 出口智代; 関口富美子; 山岨大智; 西堀正洋; 川畑篤史
    第130回日本薬理学会近畿部会  2016/11  京都
  • A role of macrophage-derived HMGB1 in paclitaxel-induced peripheral neuropathy in mice.  [Not invited]
    Domoto, R; Yamasoba, D; Yamanishi, H; Sekiguchi, F; Tsubota, M; Nishibori, M; Kawabata, A
    The 12th International Conference on Protein Phosphatase  2016/10  Higashi-Osaka, Japan
  • Interleukin-6-induced neuroendocrine-like differentiation of human prostate cancer cells: cell signaling and upregulation of Cav3.2 T-type calcium channels.  [Not invited]
    Fukami, K; Ueda, M; Asano, E; Sekiguchi, F; Yoshida, S; Kawabata, A
    The 12th International Conference on Protein Phosphatase  2016/10  Higashi-Osaka, Japan
  • Cav3.2 T-type calcium channels as therapeutic targets for the oxaliplatin-induced peripheral neuropathy.  [Not invited]
    Miyazaki, T; Fukuda, R; Tsubota, M; Kawabata, A
    The 12th International Conference on Protein Phosphatase  2016/10  Higashi-Osaka, Japan
  • Molecular mechanisms for the upregulation of Cav3.2 T-type calcium channels in the neuropathic pain.  [Not invited]
    Tomita, S; Sekiguchi, F; Tsubota, M; Kawabata, A
    The 12th International Conference on Protein Phosphatase  2016/10  Higashi-Osaka, Japan
  • Targeting HMGB1 and its downstream molecules for treatment of oxaliplatin-induced peripheral neuropathy.  [Not invited]
    Tsubota, M; Fukuda, R; Miyazaki, T; Domoto, R; Kamitani, N; Nishida, T; Sekiguchi, F; Ishikura, H; Nishibori, M; Kawabata, A
    The 12th International Conference on Protein Phosphatase  2016/10  Higashi-Osaka, Japan
  • 神経前駆様NG108-15細胞において新規T型Ca2+チャネル阻害薬6-prenylnaringeninはカンナビノイドCB1受容体を介して神経突起伸長を促進する．  [Not invited]
    野田紗友理; 大野菫; 関口富美子; 村田和也; 松田秀秋; Nguyen, H; D; 豊岡尚樹; 川畑篤史
    第66回 日本薬学会近畿支部総会・大会  2016/10  高槻
  • 新規T型カルシウムチャネル阻害薬6-prenylnaringeninのイオンチャネル選択性に関する検討：2S体とラセミ体の比較．  [Not invited]
    洞口大和; 山岡 桜; 大野 菫; 関口富美子; Nguyen, H; D; 藤田友代; 村田和也; 松田秀秋; 吉田 繁; 大久保つや子; 豊岡尚樹; 川畑篤史
    第66回 日本薬学会近畿支部総会・大会  2016/10  高槻
  • Butyrate誘起過敏性腸症候群モデルマウスにおける結腸痛覚過敏へのCav3.2 T型Ca2+チャネルの関与．  [Not invited]
    中野真希; 松井和樹; 石井優子; 坪田真帆; 川畑篤史
    第66回 日本薬学会近畿支部総会・大会  2016/10  高槻
  • マウスの坐骨神経部分結紮誘起神経障害性疼痛には知覚神経におけるCav3.2 T型カルシウムチャネルの発現増加が関与する：転写因子Egr-1および脱ユビキチン化酵素USP5の役割．  [Not invited]
    式見仕勇; 冨田詩織; 関口富美子; 坪田真帆; 岸岡史郎; 川畑 篤史
    第66回 日本薬学会近畿支部総会・大会  2016/10  高槻
  • 6-Prenylnaringeninをリード化合物とした新規T型Ca2+チャネル阻害薬の探索：電気生理学的検討．  [Not invited]
    山岡桜; 洞口大和; Nguyen, H.D; 北村 駿; 岡田卓哉; 大野 菫; 関口富美子; 西川裕之; 吉田 繁; 村田和也; 松田秀秋; 大久保つや子; 豊岡尚樹; 川畑篤史
    第66回 日本薬学会近畿支部総会・大会  2016/10  高槻
  • Mechanisms of Cav3.2 upregulation in neuropathic pain models.  [Not invited]
    Tomita, S
    2016 International Calcium channel Meeting  2016/10  Hoi An, Vietnam
  • Involvement of Cav3.2 T-type Ca2+channels in the oxaliplatin-induced neuropathic pain.  [Not invited]
    Tsubota, M
    2016 International Calcium channel Meeting  2016/10  Hoi An, Vietnam
  • Impact of zinc or ascorbic acid deficiency on Cav3.2-dependent pain.  [Not invited]
    Kawabata, A
    2016 International Calcium channel Meeting  2016/10  Hoi An, Vietnam
  • Macrophage-derived HMGB1 participates in lipopolysaccharide-induced inflammatory hyperalgesia and paclitaxel-induced neuropathic pain in mice.  [Not invited]
    Domoto, R; Yamasoba, D; Yamanishi, H; Sekiguchi, F; Tsubota, M; Nishibori, M; Kawabata, A
    16th World Congress on Pain  2016/09  Yokohama, Japan
  • Cav3.2 T-type calcium channels contribute to oxaliplatin-induced neuropathic pain in mice.  [Not invited]
    Miyazaki, T; Fukuda, R; Tsubota, M; Kawabata, A
    16th World Congress on Pain  2016/09  Yokohama, Japan
  • Tacrolimus causes relapse of pancreatic pain through TRPV1 activation during the recovery from cerulein-induced pancreatitis in mice.  [Not invited]
    Terada, Y; Tsubota, M; Sekiguchi, F; Wada, K; Kuwahara, T; Takada, M; Kawabata, A
    16th World Congress on Pain  2016/09  Yokohama, Japan
  • Roles of TLR4 and RAGE targeted by high mobility group box 1 in inflammatory and chemotherapy-induced peripheral neuropathy.  [Not invited]
    Kawabata, A
    16th World Congress on Pain  2016/09  Yokohama, Japan
  • HMGB1研究の新展開 〜免疫系と神経系のクロストークにおける役割〜．  [Not invited]
    川畑篤史
    第31回日本救命医療学会総会・学術集会  2016/09  福岡
  • トロンボモジュリンアルファの内臓痛治療への応用．  [Not invited]
    川畑篤史
    第44回日本潰瘍学会  2016/09  旭川
  • Oxaliplatin誘起神経障害性疼痛へのCav3.2 T型カルシウムチャネルの関与．  [Not invited]
    坪田真帆; 福田亮太郎; 宮崎貴也; 川畑篤史
    生体機能と創薬シンポジウム2016  2016/08  仙台
  • シクロホスファミド誘起膀胱痛にはマクロファージ由来HMGB1によるRAGEを介するH2S産生酵素の発現誘導が関与する．  [Not invited]
    平本志於里; 山口薫; 坪田真帆; 田中潤一; 関口富美子; 石倉宏恭; 西堀正洋; 川畑篤史
    生体機能と創薬シンポジウム2016  2016/08  仙台
  • Oxaliplatin誘起神経障害性疼痛の発現メカニズムの解析：HMGB1とその標的分子の関与について．  [Not invited]
    坪田真帆; 福田亮太郎; 宮崎貴也; 堂本莉紗; 上谷夏生; 西田武司; 関口富美子; 石倉宏恭; 西堀正洋; 川畑篤史
    生体機能と創薬シンポジウム2016  2016/08  仙台
  • Oxaliplatin誘起神経障害性疼痛へのHMGB1の関与：その由来と標的分子について．  [Not invited]
    坪田真帆; 福田亮太郎; 宮崎貴也; 川畑篤史
    次世代を担う創薬・医療薬理シンポジウム2016  2016/08  仙台
  • シクロホスファミド誘起間質性膀胱炎様マウスにおける膀胱痛に関与するHMGB1/RAGE系とH2S/Cav3.2系の相互関係．  [Not invited]
    平本志於里; 山口薫; 坪田真帆; 田中潤一; 関口富美子; 石倉宏恭; 西堀正洋; 川畑篤史
    次世代を担う創薬・医療薬理シンポジウム2015  2016/08  仙台
  • High mobility group box 1 mediates substance P-induced bladder pain in mice, a model for bladder pain syndrome.  [Not invited]
    Maeda, M; Irie, Y; Tsubota, M; Kubo, L; Sekiguchi, F; Ishikura, H; Nishibori, M; Kawabata, A
    Physiology 2016  2016/07  Dublin, Ireland
  • Macrophage-derived high mobility group box 1 mediates H2S-dependent bladder pain in mice with cyclophosphamide-induced cystitis.  [Not invited]
    Hiramoto, S; Tsubota, M; Yamguchi, K; Tanaka, J; Sekiguchi, F; Ishikura, H; Nishibori, M; Kawabata, A
    Physiology 2015  2016/07  Dublin, Ireland
  • Involvement of macrophage-derived high mobility group box 1 in paclitaxel-induced neuropathic pain in mice.  [Not invited]
    Domoto, R; Yamasoba, D; Yamanishi, H; Sekiguchi, F; Tsubota, M; Nishibori, M; Kawabata, A
    Physiology 2014  2016/07  Dublin, Ireland
  • Macrophage-derived high mobility group box 1 enhances neuritogenesis via NMDA receptors in neuron-like NG108-15 cells.  [Not invited]
    Sekiguchi, F; Sugimoto, R; Imanishi, M; Ueda, N; Kawabata, A
    Physiology 2013  2016/07  Dublin, Ireland
  • High mobility group box 1 mediates pancreatic pain in mice.  [Not invited]
    Kawabata, A; Irie, Y; Tsubota, M; Sekiguchi, F; Ishikura, H; Nishibori, M
    Physiology 2012  2016/07  Dublin, Ireland
  • 結腸痛の発症における侵害受容ニューロン発現分子TRPV1、PAR2およびCav3.2の役割について．  [Not invited]
    松井和樹; 中野真希; 石井優子; 寺田侑加; 坪田真帆; 川畑篤史
    第129回日本薬理学会近畿部会  2016/06  広島
  • マウス後根神経節細胞において硫化水素ドナーおよび膜透過性cyclic AMPアナログはT型Ca2+チャネルを介して神経突起伸長を誘起する：細胞サイズによる効果の違いについて．  [Not invited]
    天羽一騎; 大野菫; 関口富美子; 川畑篤史
    第129回日本薬理学会近畿部会  2016/06  広島
  • Oxaliplatin誘起神経障害性疼痛にはマクロファージ以外の細胞に由来するHMGB1が関与する．  [Not invited]
    坪田真帆; 福田亮太郎; 宮崎貴也; 西田武司; 石倉宏恭; 西堀正洋; 川畑篤史
    第129回日本薬理学会近畿部会  2016/06  広島
  • マクロファージ由来HMGB1はlipopolysaccharide誘起炎症性疼痛とpaclitaxel誘起神経障害性疼痛に関与する．  [Not invited]
    堂本莉紗; 山岨大智; 山西広樹; 関口富美子; 坪田真帆; 西堀正洋; 川畑篤史
    第38回日本疼痛学会  2016/06  札幌
  • ラットあるいはマウスの神経障害性疼痛に関与する一次知覚神経におけるCav3.2 T型Ca2+チャネルの発現誘導メカニズム．  [Not invited]
    冨田詩織; 式見志勇; 関口富美子; 坪田真帆; 川畑篤史
    第38回日本疼痛学会  2016/06  札幌
  • T-type calcium channels and neuropathic/visceral pain. Symposium entitled “Ion channels and pain: current research trends” organized by Kawabata, Tanabe and Zamponi,  [Not invited]
    Kawabata, A
    日本薬学会第136年会  2016/03  横浜
  • Cyclophosphamide誘起膀胱炎・膀胱痛マウスにおける硫化水素/T型Ca2+チャネル系の役割-下部尿路機能障害に対する新たな治療標的分子としての可能性-．院生シンポジウム「次世代若手研究者の挑戦！〜難治性疾患に対する新たな創薬ストレテジー〜」（オーガナイザー：福重・尾崎）  [Not invited]
    尾崎友香; 坪田真帆; 川畑篤史
    日本薬学会第136年会  2016/03  横浜
  • 亜鉛キレーターはT型Ca2+チャネルの機能増強によりcyclophosphamide誘起膀胱炎に伴う膀胱痛を増強する．  [Not invited]
    松岡順紀; 尾崎友香; 坪田真帆; 川畑篤史
    第89回日本薬理学会年会  2016/03  横浜
  • 末梢組織中においてレドックス状態の異なるHMGB1により誘起される痛覚過敏メカニズムの相違．  [Not invited]
    坪田真帆; 山岨大智; 堂本莉紗; 関口富美子; 西堀正洋; 川畑篤史
    第89回日本薬理学会年会  2016/03  横浜
  • 神経およびマクロファージ由来HMGB1はNMDA受容体を介して神経前駆様NG108-15細胞の神経突起伸張を促進する．  [Not invited]
    関口富美子; 杉本 陵; 今西未己; 川畑篤史
    第89回日本薬理学会年会  2016/03  横浜
  • Substance P誘起間質性膀胱炎／膀胱痛症候群モデルマウスにおけるマクロファージ由来HMGB1の役割．  [Not invited]
    前田真理子; 入江悠平; 坪田真帆; 久保里紗; 関口富美子; 石倉宏恭; 西堀正洋; 川畑篤史
    第89回日本薬理学会年会  2016/03  横浜
  • 新規T型Ca2+チャネル阻害薬sophoraflavanone Gと6-prenylnaringeninの薬理作用解析：電気生理学的性質の違いとマウスにおける痛覚過敏抑制作用．  [Not invited]
    大野 菫; 山岡 桜; 関口富美子; 市井真貴; 藤田友代; 出口貴浩; 坪田真帆; 西川裕之; 吉田 繁; 村田和也; 松田秀秋; 豊岡尚樹; 大久保つや子; 川畑篤史
    第89回日本薬理学会年会  2016/03  横浜
  • 亜鉛欠乏により誘起されるマウス痛覚過敏：Cav3.2 T型Ca2+チャネルとhigh mobility group box 1の関与．  [Not invited]
    冨田詩織; 式見仕勇; 関口富美子; 坪田真帆; 白井亮洋; 西堀正洋; 川畑篤史
    第89回日本薬理学会年会  2016/03  横浜
  • 急性膵炎に伴う膵臓痛へのマクロファージ由来HMGB 1の関与：RAGEおよびCXCR4の標的分子としての役割．  [Not invited]
    入江悠平; 坪田真帆; 関口富美子; 石倉宏恭; 西堀正洋; 川畑篤史
    第89回日本薬理学会年会  2016/03  横浜
  • マクロファージ由来high mobility group box 1はセルレイン誘起急性膵炎およびサブスタンスP誘起間質性膀胱炎/膀胱痛症候群モデルにおける内臓痛に関与する．  [Not invited]
    入江悠平; 坪田真帆; 関口富美子; 石倉宏恭; 西堀正洋; 川畑篤史
    痛み研究会2015  2015/12  岡崎
  • 神経障害性疼痛モデル動物の後根神経節におけるCav3.2 T型カルシウムチャネルの発現誘導メカニズムの解析．  [Not invited]
    冨田詩織; 式見志勇; 関口富美子; 坪田真帆; 川畑篤史
    痛み研究会2015  2015/12  岡崎
  • Sophoraflavanone Gとその類縁体6-prenylnaringeninのT型Ca2+チャネル阻害作用の電気生理学的特徴と各種疼痛モデルでの有効性．  [Not invited]
    大野菫; 山岡桜; 関口富美子; 市井真貴; 藤田友代; 出口貴浩; 坪田真帆; 西川浩之; 吉田繁; 村田和也; 松田秀秋; 豊岡尚樹; 大久保つや子; 川畑篤史
    第128回日本薬理学会近畿部会  2015/11  豊中
  • Cyclophosphamide誘起膀胱炎マウスにおける膀胱痛は亜鉛欠乏により増強される：T型Ca2+チャネルの関与について．  [Not invited]
    尾崎友香; 松岡順紀; 坪田真帆; 冨田詩織; 関口富美子; 南武志; 川畑篤史
    第128回日本薬理学会近畿部会  2015/11  豊中
  • High mobility group box 1はsubstance P誘起膀胱痛症候群モデルマウスにおける関連痛覚過敏の発現・維持に関与する．  [Not invited]
    入江悠平; 前田真理子; 久保理沙; 坪田真帆; 関口富美子; 石倉宏恭; 西堀正洋; 川畑篤史
    第128回日本薬理学会近畿部会  2015/11  豊中
  • マクロファージ由来high mobility group box 1はマウスにおけるlipopolysaccharide誘起炎症性痛覚過敏及び抗癌剤paclitaxel誘起神経障害性疼痛に関与する．  [Not invited]
    堂本莉紗; 山岨大智; 山西広樹; 関口富美子; 坪田真帆; 西堀正洋; 川畑篤史
    第128回日本薬理学会近畿部会  2015/11  豊中
  • Molecular mechanisms for the upregulation of Cav3.2 T-type calcium channels in the dorsal root ganglion of rats with spinal nerve injury-induced neuropathy: involvement of Egr-1 and USP5.  [Not invited]
    Tomita, S; Sekiguchi, F; Tsubota, M; Kawabata, A
    Neuroscience 2015  2015/10  Chicago, USA
  • The electrophysiological property and antihyperalgesic activity of sophoraflavanone G and 6prenylnaringenin, novel T-type calcium channel blockers.  [Not invited]
    Ono, S; Ichii, M; Yamaoka, S; Sekiguchi, F; Fujita, T; Deguchi, T; Tsubota, M; Nishikawa, H; Yoshida, S; Murata, K; Matsuda, H; Toyooka, N; Ohkubo, T; Kawabata, A
    Neuroscience 2015  2015/10  Chicago, USA
  • Chronic stress enhances the hyperthermia in response to acute restraint stress.  [Not invited]
    Miyamato, T; Funakami, Y; Kawasita, E; Nomura, A; Sugimoto, N; Ichida, S; Kawabata, A
    Neuroscience 2015  2015/10  Chicago, USA
  • Zinc deficiency aggravates bladder pain accompanying cyclophosphamide-induced cystitis through the enhanced activity of Cav3.2 T-type Ca2+ channels in mice.  [Not invited]
    Ozaki, T; Matsuoka, J; Tsubota, M; Tomita, S; Sekiguchi, F; Minami, T; Kawabata, A
    Neuroscience 2015  2015/10  Chicago, USA
  • Macrophage-derived high mobility group box 1 participates in the development and maintenance of pancreatic pain through the activation of RAGE and CXCR4 in mice with cerulein-induced acute pancreatitis.  [Not invited]
    Irie, Y; Tsubota, M; Sekiguchi, F; Ishikura, H; Nishibori, M; Kawabata, A
    Neuroscience 2015  2015/10  Chicago, USA
  • Hydrogen sulfide and intracellular cyclic AMP enhance T-type calcium channel-dependent neurite outgrowth in distinct subpopulations of isolated and dissociated mouse dorsal root ganglion neurons.  [Not invited]
    Sekiguchi, F; Amo, I; Ono, S; Kawabata, A
    Neuroscience 2015  2015/10  Chicago, USA
  • Bladder pain accompanying cyclophosphamide-induced mouse cystitis involves HMGB1 release upstream of the cystathionine-gamma-lyase/H2S/Cav3.2 pathway in the bladder tissue.  [Not invited]
    Kawabata, A; Tsubota, M; Yamaguchi, K; Hiramoto, S; Sekiguchi, F; Tanaka, J; Ishikura, H; Nishibori, M
    Neuroscience 2015  2015/10  Chicago, USA
  • 硫化水素によって惹起された外有毛細胞のTRPV4受容体を介したストア作動性カルシウム流入  [Not invited]
    原田成信; 伊藤由香里; 高嶋一平; 王子田彰夫; 川畑篤史
    第25回日本耳科学会総会  2015/10  長崎
  • Vitamin C deficiency aggravates hydrogen sulfide-induced pain/hyperalgesia and chemotherapy-induced neuropathy in mice: possible involvement of T-type calcium channels.  [Not invited]
    Kawabata, A; Tsubota, M; Uebo, K; Miki, K; Sekiguchi, F; Fukuda, R; Kondo, Y; Takahashi, K; Masutomi, H; Ishigami, A
    9th Congress of the European Pain Federation EFIC  2015/09  Vienna
  • ラット第5腰神経切断により誘起される神経障害性疼痛および脊髄後根神経節におけるCav3.2 T型Ca2+チャネル発現増加への転写調節因子Egr-1と脱ユビキチン化酵素USP5の関与  [Not invited]
    冨田詩織; 関口富美子; 坪田真帆; 川畑篤史
    生体機能と創薬シンポジウム2015  2015/08  船橋
  • 新規T型カルシウムチャネル阻害薬sophoraflavanone Gおよび6-prenylnaringeninの電気生理学的性質と痛覚過敏抑制効果  [Not invited]
    大野 菫; 市井真貴; 山岡 桜; 関口富美子; 藤田友代; 出口貴浩; 坪田真帆; 西川裕之; 吉田 繁; 村田和也; 松田秀秋; 豊岡尚樹; 大久保つや子; 川畑篤史
    生体機能と創薬シンポジウム2015  2015/08  船橋
  • 内臓痛の新しい治療標的分子：T型Ca2+チャネルとHMGB1  [Not invited]
    川畑篤史
    生体機能と創薬シンポジウム2015  2015/08  船橋
  • PAR2と痛み  [Not invited]
    川畑篤史
    日本ペインクリニック学会第49回大会  2015/07  大阪
  • Cerulein誘起マウス急性膵炎モデルにおける膵臓痛の発現・維持にはマクロファージ由来high mobility group box 1によるRAGEおよびCXCR4の活性化が関与する  [Not invited]
    入江悠平; 坪田真帆; 関口富美子; 石倉宏恭; 西堀正洋; 川畑篤史
    第127回日本薬理学会近畿部会  2015/06  岐阜
  • Butyrate誘起過敏性腸症候群モデルマウスにおける結腸痛覚過敏へのT型Ca2+チャネルおよびHMGB1の関与  [Not invited]
    坪田真帆; 石井優子; 中野真希; 梶谷梨絵; 西堀正洋; 川畑篤史
    第127回日本薬理学会近畿部会  2015/06  岐阜
  • シクロホスファミド誘起膀胱炎マウスにおけるポラプレジンクの予防・治療効果  [Not invited]
    村上(中山)雅裕; 昼馬佐紀; 坪田真帆; 関口富美子; 松山賢治; 木村健; 森山雅弘; 川畑篤史
    日本薬学会第135年会  2015/03  神戸
  • 高グルコース条件下で培養した神経内分泌様分化ヒト前立腺癌LNCaP細胞におけるCav3.2 T型Ca2+チャネルの糖鎖修飾による機能増強と分泌機能亢進  [Not invited]
    浅野絵莉茄; 深海和樹; 関口富美子; 泰川未来; 笠松隆二; 吉田繁; 川畑篤史
    日本薬学会第135年会  2015/03  神戸
  • HMGB1はoxaliplatin誘起神経障害性疼痛の発現および維持に関与する  [Not invited]
    福田亮太郎; 山西広樹; 坪田真帆; 関口富美子; 西田武司; 石倉宏恭; 西堀正洋; 川畑篤史
    日本薬学会第135年会  2015/03  神戸
  • マウス後根神経節細胞において硫化水素ドナーNa2SはT型Ca2+チャネルを介して神経突起伸長を促進する：細胞の大きさによる効果の違いについて  [Not invited]
    天羽一騎; 大野 菫; 関口富美子; 川畑篤史
    日本薬学会第135年会  2015/03  神戸
  • 急性膵炎・膵臓痛動物モデルを用いた病態解析：T型?Ca2+チャネルおよびTRPチャネルの役割  [Not invited]
    寺田侑加; 坪田真帆; 関口富美子; 和田恭一; 原健; 高田充隆; 川畑篤史
    日本薬学会第135年会  2015/03  神戸
  • 亜鉛含有製剤ポラプレジンクのcyclophosphamide誘起膀胱炎・膀胱痛に対する予防および治療効果  [Not invited]
    昼馬佐紀; 村上(中山)雅裕; 坪田真帆; 関口富美子; 松山賢治; 木村健; 森山雅弘; 川畑篤史
    第88回日本薬理学会年会  2015/03  名古屋
  • 神経障害性疼痛ラットの知覚神経におけるCav3.2 T型Ca2+チャネル発現誘導には転写因子Egr-1および脱ユビキチン化酵素USP5が関与する  [Not invited]
    冨田詩織; 関口富美子; 坪田真帆; 川畑篤史
    第88回日本薬理学会年会  2015/03  名古屋
  • マクロファージ由来HMGB1はNF-kB系を介して炎症性痛覚過敏に寄与する  [Not invited]
    山岨大智; 関由加里; 山西広樹; 坪田真帆; 関口富美子; 八木秀樹; 益子 高; 西堀正洋; 川畑篤史
    第88回日本薬理学会年会  2015/03  名古屋
  • 神経内分泌様分化した前立腺癌LNCaP細胞において高グルコース条件下でのCav3.2 T型カルシウムチャネルのN-結合型グリコシル化により分泌機能が亢進する  [Not invited]
    深海和樹; 浅野絵莉茄; 関口富美子; 泰川未来; 笠松隆二; 吉田繁; 川畑篤史
    第88回日本薬理学会年会  2015/03  名古屋
  • HMGB1を標的とする内臓痛治療  [Not invited]
    坪田真帆; 川畑篤史
    第88回日本薬理学会年会  2015/03  名古屋
  • Involvement of high mobility group box 1 in substance P-induced cystitis-related bladder pain in mice  [Not invited]
    Irie, Y; Kubo, L; Tsubota, M; Sekiguchi, F; Ishimura, H; Nishibori, M; Kawabata, A
    Pharmacology 2014  2014/12  London, UK
  • The novel cognitive enhancer ST101 induces neurite outgrowth in NG108-15 cells and hyperalgesia in mice through T-type Ca2+ channels  [Not invited]
    Ohno, S; Kanaoka, D; Ide, H; Sekiguchi, F; Yoshida, S; Fukunaga, K; Kawabata, A
    Pharmacology 2014  2014/12  London, UK
  • The NK1 receptor antagonist prevents the cyclophosphamide-induced cystitis-related bladder pain and upregulation of cystathionine-γ-lyase, an H2S-generating enzyme, in mice  [Not invited]
    Ozaki, T; Tsubota, M; Kawabata, A
    Pharmacology 2014  2014/12  London, UK
  • Effect of tacrolimus on caerulein-induced pancreatitis-related pain in mice  [Not invited]
    Terada, Y; Tsubota, M; Sekiguchi, F; Wada, K; Kuwahara, T; Takada, M; Kawabata, K
    Pharmacology 2014  2014/12  London, UK
  • High mobility group box 1 as a target for prevention and therapeutic treatment of chemotherapy-induced neuropathic pain.  [Not invited]
    Kawabata, A; Kawaishi, Y; Nishida, T; Yamanishi, H; Kamitani, N; Tsubota, M; Sekiguchi, F; Ishikura, H; Nishibori, M
    Pharmacology 2014  2014/12  London, UK
  • マクロファージ由来HMGB1の炎症性痛覚過敏への関与と分子作用メカニズムの解析  [Not invited]
    山岨大智; 関由加里; 山西広樹; 坪田真帆; 関口富美子; 八木秀樹; 益子 高; 西堀正洋; 川畑篤史
    第126回日本薬理学会近畿部会  2014/10  和歌山
  • 第5腰神経切断神経障害性疼痛ラットにおけるCav3.2 T型Ca2+チャネル発現増加機序の解析：転写調節因子Egr-1と脱ユビキチン化酵素USP5の挙動について  [Not invited]
    冨田詩織; 関口富美子; 坪田真帆; 川畑篤史
    第126回日本薬理学会近畿部会  2014/10  和歌山
  • Calcineurin阻害薬tacrolimusはcapsaicin誘起結腸痛およびcerulein誘起急性膵炎関連痛を増強する  [Not invited]
    寺田侑加; 松井和樹; 坪田真帆; 関口富美子; 和田恭一; 原 健; 田充隆; 川畑篤史
    第126回日本薬理学会近畿部会  2014/10  和歌山
  • Mechanims for upregulation of cystathionine-gamma-lyase, a hydrogen sulfide-generating enzyme, in mice with cyclophosphamide-induced cystititis: Involvement of substance P/NK1 pathway and NF-kappaB signals.  [Not invited]
    Ozaki, T; Tsubota, M; Kawabata, A
    International Symposium “Gasotransmitters: Physiology and Pathophysiology”  2014/09  Kazan, Russia
  • Hydrogen sulfide: Importance of T-type calcium channels as the molecular target  [Not invited]
    Kawabata, A
    International Symposium “Gasotransmitters: Physiology and Pathophysiology”  2014/09  Kazan, Russia
  • Capsaicin誘起結腸痛に対するcalcineurin阻害薬FK506の増強効果  [Not invited]
    松井和樹; 寺田侑加; 坪田真帆; 関口富美子; 川畑篤史
    次世代を担う創薬・医療薬理シンポジウム2014  2014/08  東大阪
  • Histone deacetylase阻害薬は内因性high mobility group box 1遊離を介して神経前駆細胞株NG108-15細胞の神経突起伸長を誘起する  [Not invited]
    杉本陵; 上田菜生; 関口富美子; 川畑篤史
    次世代を担う創薬・医療薬理シンポジウム2014  2014/08  東大阪
  • 新規T型Ca2+チャネル阻害薬RQ-00311651の電気生理学的性質および神経障害性疼痛に対する抑制効果  [Not invited]
    冨田詩織; 瓦侑馬; 関口富美子; 川石雄大; 坪田真帆; 吉田 繁; 大久保つや子; 川畑篤史
    次世代を担う創薬・医療薬理シンポジウム2014  2014/08  東大阪
  • Exploration of novel T-type Ca2+ channel inhibitors for treatment of intractable pain  [Not invited]
    Sekiguchi, F; Kawabata, A
    生体機能と創薬シンポジウム2014  2014/08  東大阪
  • ナノ化技術を用いた新規注射用製剤の開発とその有用性評価 −シロスタゾール静脈内投与による脳梗塞治療−  [Not invited]
    田辺 航; 松下 翔子; 西本 夏海; 長井 紀章; 伊藤 吉將; 西川 裕之; 川畑 篤史
    生体機能と創薬シンポジウム2014  2014/08  東大阪
  • ポラプレジンクを使用した含嗽液の安定性と放射線性口腔粘膜炎に対する臨床評価  [Not invited]
    中山雅裕; 中村豪志; 東 剛史; 松山賢治; 森山雅弘; 木村 健; 川畑篤史
    生体機能と創薬シンポジウム2014  2014/08  東大阪
  • ポラプレジンクはcyclophosphamide誘起膀胱炎マウスにおける炎症症状および膀胱痛を抑制する  [Not invited]
    昼馬佐紀; 中山雅裕; 坪田真帆; 関口富美子; 松山賢治; 木村健; 森山雅弘; 川畑篤史
    生体機能と創薬シンポジウム2014  2014/08  東大阪
  • Calcineurin阻害薬tacrolimusはTRPV1を介してcerulein誘起急性膵炎関連痛を増強する  [Not invited]
    寺田侑加; 坪田真帆; 関口富美子; 和田恭一; 桑原 健; 髙田充隆; 川畑篤史
    生体機能と創薬シンポジウム2014  2014/08  東大阪
  • ヒト可溶性トロンボモジュリンを用いた痛みの治療：HMGB1吸着・分解促進作用の関与  [Not invited]
    坪田真帆; 川畑篤史
    生体機能と創薬シンポジウム2014  2014/08  東大阪
  • Sophoraflavanone G as a novel T-type Ca2+ channel inhibitor: electrophysiological evidence in Cav3.2-expressing HEK293 cells and anti-hyperalgesic activity in mice  [Not invited]
    Sekiguchi, F; Fujita, T; Deguchi, T; Ichii, M; Yamaoka, S; Nishikawa, H; Yoshida, S; Murata, K; Matsuda, M; Ohkubo, T; Kawabata, A
    9th FENS Forum of European Neuroscience  2014/07  Milan, Italy
  • Prevention and reversal of chemotherapy-induced neuropathic pain by HMGB1 neutralization in rodents  [Not invited]
    Kawabata, A; Kawaishi, Y; Nishida, T; Yamanishi, H; Kamitani, N; Tsubota, M; Ishikura, H; Sekiguchi, F; Nishibori, M
    9th FENS Forum of European Neuroscience  2014/07  Milan, Italy
  • ヒト胃癌由来AGS細胞における内因性硫化水素の細胞増殖への関与とその下流シグナルの解析  [Not invited]
    小椋彩加; 関本晃己; 関口富美子; 川畑篤史
    第125回日本薬理学会近畿部会  2014/06  岡山
  • Cav3.2 T型Ca2+チャネルを阻害するascorbic acidの欠乏は硫化水素による体性痛・内臓痛およびpaclitaxel誘起神経障害性疼痛を増強する  [Not invited]
    上坊健太; 三木好輝; 坪田真帆; 関口富美子; 近藤嘉高; 高橋経太; 増富裕文; 石神昭人; 川畑篤史
    第125回日本薬理学会近畿部会  2014/06  岡山
  • Cyclophosphamide誘起マウス膀胱炎モデルにおける膀胱痛発症メカニズムの解析：核内蛋白HMGB1と内因性H2Sの役割  [Not invited]
    山口薫; 田中潤一; 坪田真帆; 関口富美子; 関由加里; 石倉宏恭; 西堀正洋; 川畑篤史
    第125回日本薬理学会近畿部会  2014/06  岡山
  • 可溶性トロンボモジュリンおよび抗HMGB1中和抗体はlipopolysaccharideあるいはsubstance P膀胱内注入により誘起される膀胱痛を抑制する  [Not invited]
    久保里紗; 坪田真帆; 関口富美子; 石倉宏恭; 西堀正洋; 川畑篤史
    第125回日本薬理学会近畿部会  2014/06  岡山
  • 新規T型Ca2+チャネル阻害薬sophoraflavanone Gの薬理学的特徴と痛覚過敏抑制効果  [Not invited]
    関口富美子; 川畑篤史
    第36回日本疼痛学会  2014/06  大阪
  • Roles of hydrogen sulfide and T-type calcium channels in neuroendocrine-differentiated prostate cancer cells at androgen-independent stage  [Not invited]
    Fukami, K; Kawabata, A
    Anti-Aging International Mini-Symposium 2014: Cell Signaling and Therapeutic Targets for Geriatric and Inflammatory Diseases  2014/06  Higashi-Osaka
  • Ascorbic acid deficiency augments hyperalgesia induced by hydrogen sulfide in mice  [Not invited]
    Tsubota, M; Uebo, K; Miki, K; Sekiguchi, F; Kondo, Y; Takahashi, K; Masutomi, H; Ishigami, A; Kawabata, A
    Third International Conference on Hydrogen Sulfide in Biology and Medicine  2014/06  Kyoto
  • Involvement of endogenous hydrogen sulfide and T-type calcium channels in cyclic AMP-induced neuronal differentiation in NG108-15 cells  [Not invited]
    Sekiguchi, F; Takeda, Y; Kanaoka, D; Yoshida, S; Kawabata, A
    Third International Conference on Hydrogen Sulfide in Biology and Medicine  2014/06  Kyoto
  • Roles of the hydrogen sulfide-Cav3.2 T-type calcium channel pathway in neuronal and neuroendocrine differentiation  [Not invited]
    Kawabata, A
    Third International Conference on Hydrogen Sulfide in Biology and Medicine  2014/06  Kyoto
  • 結腸の疼痛および炎症におけるガス状情報伝達物質硫化水素の役割  [Not invited]
    坪田真帆; 川畑篤史
    日本薬学会第134年会  2014/03  熊本
  • Roles of Cav3.2 T-type Ca2+ channels in prostate cancer cells: impact on an androgen-independent stage  [Not invited]
    Kawabata, A
    第87回日本薬理学会年会  2014/03  仙台
  • 中和抗体と遺伝子組換えヒト可溶性トロンボモジュリンによるHMGB1不活化はラットおよびマウスにおけるパクリタキセル誘起神経障害性疼痛を抑制する  [Not invited]
    川石雄大; 山西広樹; 坪田真帆; 関口富美子; 西田武司; 石倉宏恭; 西堀正洋; 川畑篤史
    第87回日本薬理学会年会  2014/03  仙台
  • 新規認知機能改善薬ST101により誘起されるNG108-15細胞における神経突起伸長促進作用とマウスにおける痛覚過敏へのT型Ca2+チャネルの関与  [Not invited]
    大野 菫; 金岡大樹; 井手洋樹; 関口富美子; 吉田 繁; 福永浩司; 川畑篤史
    第87回日本薬理学会年会  2014/03  仙台
  • カルシニューリン阻害薬タクロリムスはカプサイシン誘起結腸痛を増強する  [Not invited]
    寺田侑加; 坪田真帆; 関口富美子; 和田恭一; ?原 健; 田充隆; 川畑篤史
    第87回日本薬理学会年会  2014/03  仙台
  • 苦参由来sophoraflavanone Gおよびその類縁体のT型カルシウムチャネル阻害活性と痛覚過敏抑制効果  [Not invited]
    関口富美子; 藤田友代; 出口貴浩; 市井真貴; 西川裕之; 吉田 繁; 村田和也; 松田秀秋; 大久保つや子; 川畑篤史
    第87回日本薬理学会年会  2014/03  仙台
  • ビンクリスチン誘起神経障害性疼痛ラットにおける抗HMGB1中和抗体と遺伝子組換えヒト可溶性トロンボモジュリンの予防・治療効果  [Not invited]
    西田武司; 川石雄大; 山西広樹; 坪田真帆; 関口富美子; 石倉宏恭; 西堀正洋; 川畑篤史
    第87回日本薬理学会年会  2014/03  仙台
  • Involvement of high mobility group box 1 in cyclophosphamide-induced cystitis-related bladder pain in mice.  [Not invited]
    Kawabata, A; Tanaka, J; Yamaguchi, K; Ishikura, H; Tsubota, M
    Pharmacology 2013  2013/12  London, UK
  • Recombinant human soluble thrombomodulin abolishes bladder pain accompanying cyclophosphamide-induced cystitis in mice  [Not invited]
    Tanaka, J; Ishikura, H; Yamaguchi, K; Tsubota, M; Sekiguchi, F; Seki, Y; Kawabata, A
    Neuroscience 2013  2013/11  San Diego, USA
  • Roles of TRPA1 channels in addition to Cav3.2 or TRPV1 as the downstream signal of hydrogen sulfide or proteinase-activated receptor-2 in the development of pancreatic pain  [Not invited]
    Terada, Y; Fujimura, M; Nishimukra, S; Tsubota, M; Kawabata, A
    Neuroscience 2013  2013/11  San Diego, USA
  • RQ-00311651, a novel T-type Ca2+ channel blocker: electrophysiological characterization and anti-hyperalgesic/anti-allodynic activity in somatic and visceral pain models.  [Not invited]
    Sekiguchi, F; Kawara, Y; Kanaoka, D; Kawaishi, Y; Tsubota, M; Kawakami, E; Ozaki, T; Yoshida, S; Okubo, T; Kawabata, A
    Neuroscience 2013  2013/11  San Diego, USA
  • Facilitation of T-type calcium currents by endogenous and exogenous hydrogen sulfide in Cav3.2-expressing HEK293 cells  [Not invited]
    Kawabata, A; Miyamoto, Y; Sekiguchi, F; Kanaoka, D; Yoshida, S; Ohkubo, T
    Neuroscience 2013  2013/11  San Diego, USA
  • マウスにおいてprostaglandin E2により誘起されるT型Ca2+チャネルを介する機械的痛覚過敏の特徴：EP2/PKA経路における足場タンパクAKAP150の重要性とEP1/PKC経路の関与について  [Not invited]
    竹中秀; 中村早織; 坪田真帆; 関口富美子; 川畑篤史
    第124回日本薬理学会近畿部会  2013/11  京都
  • Cav3.2 T型Ca2+チャネル発現HEK293細胞において内因性および外因性硫化水素はチャネル機能を増強する  [Not invited]
    関口富美子; 宮本陽介; 金岡大樹; 井手洋樹; 吉田 繁; 大久保つや子; 川畑篤史
    第124回日本薬理学会近畿部会  2013/11  京都
  • 新規認知機能改善薬ST101はT型Ca2+チャネルを介してNG108-15細胞における神経突起伸長とマウスにおける痛覚過敏を誘起する  [Not invited]
    大野 菫; 金岡大樹; 井手洋樹; 関口富美子; 吉田 繁大野; 金岡大樹; 井手洋樹; 関口富美子; 吉田 繁; 福永浩司; 川畑篤史
    生体機能と創薬シンポジウム2013  2013/08  福岡
  • シクロホスファミド誘起膀胱炎マウスにおけるヒト可溶性トロンボモジュリンの膀胱痛抑制効果：HMGB1吸着・不活化作用の関与  [Not invited]
    山口薫; 田中潤一; 関由加里; 石倉宏恭; 坪田真帆; 関口富美子; 川畑篤史
    生体機能と創薬シンポジウム2013  2013/08  福岡
  • ヒト可溶性トロンボモジュリンはHMGB1シグナルを抑制することで炎症性疼痛を抑制する  [Not invited]
    関由加里; 田中潤一; 山口薫; 石倉宏恭; 坪田真帆; 関口富美子; 川畑篤史
    生体機能と創薬シンポジウム2013  2013/08  福岡
  • NG108-15細胞におけるdibutyryl cyclic AMP誘起神経分化への内因性硫化水素とCav3.2 T型Ca2+チャネルの関与  [Not invited]
    竹田優希; 金岡大樹; 関口富美子; 吉田繁; 川畑篤史
    生体機能と創薬シンポジウム2013  2013/08  福岡
  • Lipopolysaccharide膀胱内注入により誘起されるマウス膀胱炎・膀胱痛に対する可溶性トロンボモジュリンの効果：投与量による違い  [Not invited]
    久保里紗; 坪田真帆; 関口富美子; 石倉宏恭; 西堀正洋; 川畑篤史
    生体機能と創薬シンポジウム2013  2013/08  福岡
  • マウスにおけるCav3.2 T型Ca2+チャネルを介する硫化水素の痛み促進効果はアスコルビン酸欠乏により増大する：SMP30/GNLノックアウトマウスを用いた検討  [Not invited]
    上坊健太; 三木好輝; 坪田真帆; 関口富美子; 近藤嘉高; 高橋経太; 増富裕文; 石神昭人; 川畑篤史
    生体機能と創薬シンポジウム2013  2013/08  福岡
  • 膵臓痛発現におけるH2S下流シグナル分子としてのCav3.2およびTRPA1の役割：健常時と急性膵炎発症時の違い  [Not invited]
    寺田侑加; 藤村茉由子; 西村幸容; 坪田真帆; 川畑篤史
    生体機能と創薬シンポジウム2013  2013/08  福岡
  • TRPA1はPAR2の下流シグナル分子としてTRPV1とともに膵炎関連痛覚過敏の発症・維持に寄与する  [Not invited]
    寺田侑加; 藤村茉由子; 西村幸容; 坪田真帆; 川畑篤史
    生体機能と創薬シンポジウム2013  2013/08  福岡
  • シクロホスファミド誘起膀胱炎・膀胱痛に対するNK1受容体拮抗薬およびcurcuminの効果：硫化水素 / T型カルシウムチャネル系の上流シグナルの解析  [Not invited]
    尾崎友香; 坪田真帆; 西浦佳那恵; 川畑篤史
    第123回日本薬理学会近畿部会  2013/07  名古屋
  • 苦参由来T型Ca2+チャネル阻害物質の検索：ヒトCav3.2発現HEK293細胞における電気生理学的検討とマウスにおける硫化水素誘起痛覚過敏に対する抑制効果の評価  [Not invited]
    藤田友代; 関口富美子; 出口貴浩; 吉田 繁; 村田和也; 松田秀秋; 大久保つや子; 川畑篤史
    第123回日本薬理学会近畿部会  2013/07  名古屋
  • ヒト前立腺癌由来LNCaP細胞におけるcyclic AMP誘起神経内分泌様分化に伴うH2S/Cav3.2系の機能増強とその分子メカニズム  [Not invited]
    泰川未来; 深海和樹; 笠松隆二; 関口富美子; 吉田 繁; 川畑篤史
    第123回日本薬理学会近畿部会  2013/07  名古屋
  • 遺伝子組換えヒト可溶性トロンボモジュリンはHMGB1シグナルを抑制することでパクリタキセル誘起神経障害性疼痛モデルにおいて予防および治療効果を示す  [Not invited]
    川石雄大; 山西広樹; 坪田真帆; 西堀正洋; 石倉宏恭; 川畑篤史
    第123回日本薬理学会近畿部会  2013/07  名古屋
  • 新規T型Ca2+チャネル阻害薬RQ-00311651の電気生理学的特徴と体性痛・内臓痛モデルにおける鎮痛効力  [Not invited]
    関口富美子; 坪田真帆; 川畑篤史
    第35回日本疼痛学会  2013/07  さいたま
  • 遺伝子組換えヒト可溶性トロンボモジュリンの炎症性疼痛および癌化学療法誘起神経障害性疼痛に対する予防・治療効果：HMGB1吸着・不活化作用の関与について  [Not invited]
    川畑篤史; 坪田真帆; 関口富美子
    第35回日本疼痛学会  2013/07  さいたま
  • 硫化水素の生理機能と病態への関与：特に内臓痛および内臓炎症における役割  [Not invited]
    坪田真帆; 川畑篤史
    第90回日本生理学会大会  2013/03  東京
  • Modulation of Cav3.2 T-type calcium channels by endogenous mediators: impact on pain signals and others  [Not invited]
    Kawabata, A
    3rd International Calcium Channel Conference  2013/03  Krabi, Thailand
  • 知覚神経細胞におけるcyclic AMP誘起神経突起伸長に対するT型Ca2+チャネルおよびK+チャネルの関与  [Not invited]
    前田貴史; 山縣亮介; 三谷健治; 田中友香里; 関口富美子; 川畑篤史
    第122回日本薬理学会近畿部会  2012/11  豊中
  • NG108-15細胞とラット後根神経節細胞におけるCav3.2 T型Ca2+チャネル機能のcyclic AMP依存性増強メカニズムの解析  [Not invited]
    金岡大樹; 山中瑠美; 関口富美子; 吉田 繁; 川畑篤史
    第122回日本薬理学会近畿部会  2012/11  豊中
  • 遺伝子組み換え可溶性ヒト・トロンボモジュリンのマウス間質性膀胱炎モデルにおける膀胱痛抑制効果  [Not invited]
    田中潤一; 山口 薫; 関由加里; 石倉宏恭; 坪田真帆; 関口富美子; 川畑篤史
    第122回日本薬理学会近畿部会  2012/11  豊中
  • 新規T型Ca2+チャネル阻害薬RQ-00311651は各種内臓痛を抑制する  [Not invited]
    坪田真帆; 川上絵理; 尾崎友香; 関口富美子; 井上 義; 奥村貴子; 川畑篤史
    第122回日本薬理学会近畿部会  2012/11  豊中
  • 新規T型Ca2+チャネル阻害薬RQ-00311651のチャネル阻害効果の特徴および体性痛覚過敏に対する抑制効果  [Not invited]
    関口富美子; 瓦 侑馬; 金岡大樹; 川石雄大; 坪田真帆; 吉田 繁; 大久保つや子; 山澤美緒; 我謝徳一; 大城博行; 井上 義; 川畑篤史
    第122回日本薬理学会近畿部会  2012/11  豊中
  • Roles of endogenous hydrogen sulfide in the cyclic AMP-induced neuronal differentiation in NG108-15 cells  [Not invited]
    Kanaoka, D; Takeda, Y; Sekiguchi, F; Yoshida, S; Kawabata, A
    Neuroscience 2012  2012/10  New Orleans, USA
  • Molecular mechanisms for the neurite outgrowth caused by prostaglandin E2 in mouse dorsal root ganglion cells  [Not invited]
    Maeda, T; Mitani, K; Yamagata, R; Sekiguchi, F; Kawabata, A
    Neuroscience 2012  2012/10  New Orleans, USA
  • Recombinant soluble human thrombomodulin abolishes inflammatory hyperalgesia in rats  [Not invited]
    Tanaka, J; Seki, Y; Yamaguchi, K; Ishikura, H; Tsubota, M; Sekiguchi, F; Kawabata, A
    Neuroscience 2012  2012/10  New Orleans, USA
  • Blocking T-type calcium channels protects against the brain injury induced by middle cerebral artery occlusion and reperfusion in mice  [Not invited]
    Kawabata, A; Nishikawa, H; Matsuda, S; Fukatsu, A; Kurokawa, Y; Tsubota-Matsunami, M; Tokuyama, S
    Neuroscience 2012  2012/10  New Orleans, USA
  • Roles of endogenous hydrogen sulfide in proliferation of gastric cancer cells.  [Not invited]
    Sekiguchi, F; Sekimoto, T; Ogura, A; Kawabata, A
    7th International Symposium on Cell/Tissue Injury and Cyotoprotection/Organoprotection  2012/09  Honolulu, Hawaii, USA
  • Roles of Cav3.2 and TRPA1 channels targeted by hydrogen sulfide in processing of visceral pain signals in the colon, pancreas and bladder  [Not invited]
    Kawabata, A
    7th International Symposium on Cell/Tissue Injury and Cyotoprotection/Organoprotection  2012/09  Honolulu, Hawaii, USA
  • 遺伝子組換えヒト可溶性トロンボモジュリンはシクロホスファミド誘起膀胱炎マウスにおける膀胱痛を抑制する  [Not invited]
    山口薫; 田中潤一; 関由加里; 石倉宏恭; 坪田真帆; 関口富美子; 川畑篤史
    第86回日本薬理学会年会  福岡
  • 遺伝子組換えヒト可溶性トロンボモジュリンはラットにおいてHMGB1依存炎症性疼痛を抑制する  [Not invited]
    関由加里; 田中潤一; 山口薫; 石倉宏恭; 坪田真帆; 関口富美子; 川畑篤史
    第86回日本薬理学会年会  福岡
  • 新規T型カルシウムチャネル阻害薬RQ-00311651の各種内臓痛に対する治療効果  [Not invited]
    川上絵理; 坪田真帆; 尾崎友香; 関口富美子; 井上義; 奥村貴子; 川畑篤史
    第86回日本薬理学会年会  福岡
  • 新規T型カルシウムチャネル阻害薬RQ-00311651：膜電流およびカルシウム流入に対する抑制効果と鎮痛効力  [Not invited]
    瓦 侑馬; 関口富美子; 金岡大樹; 川石雄大; 坪田真帆; 吉田 繁; 大久保つや子; 山澤美緒; 我謝徳一; 大城博行; 井上 義; 川畑篤史
    第86回日本薬理学会年会  福岡

MISC

Industrial Property Rights

Awards & Honors

  • 2000 日本薬学会近畿支部奨励賞
     JPN
  • 1998 Annual Award 1998 of The Pharmacological Society of Canada

Research Grants & Projects

  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2023/04 -2026/03 
    Author : 関口 富美子; 川畑 篤史; 坪田 真帆
  • 日本学術振興会：科学研究費助成事業 基盤研究(C)
    Date (from‐to) : 2021/04 -2024/03 
    Author : 川畑 篤史; 関口 富美子; 坪田 真帆
     
    2021年度は、ボルテゾミブ、パクリタキセル、オキサリプラチンなどの抗がん薬の副作用として生じる化学療法誘発性末梢神経障害（CIPN）、butyrateやTNBSなどにより誘発される過敏性腸症候群（IBS）モデルにおける内臓痛、２型糖尿病に伴う有痛性末梢神経障害に対して、遺伝子組換えヒト可溶性トロンボモジュリン（トロンボモジュリンアルファ；TMα）が予防的に作用することを検証あるいは証明した。一方、1型糖尿病の末梢神経障害に対してTMαは無効であった。また、抗凝固薬アルガトロバンは、上記痛みモデルにおけるTMαの効果を抑制した。また、TMαの抗CIPN効果にはトロンビン依存性のHMGB1不活性化作用に加えて、プロテインC（PC）およびthrombin-activatable fibrinolysis inhibitor (TAFI)の活性化が関与することを明らかにした。さらに活性化されたPC（APC）とTAFI（TAFIa）の標的分子はそれぞれproteinase-activated receptor 1 (PAR1)および補体アナフィラトキシンC5aであることも突き止めた。また、関西医科大学附属病院薬剤部との共同研究で実施した後ろ向きコホート研究により、2型糖尿病患者において有痛性末梢神経障害の発症率は、抗凝固薬投与患者の方が非投与群よりも有意に高いことを突き止め、内因性トロンビンが恐らく内皮トロンボモジュリン依存性に痛み抑制的に働いているとの仮説を支持する知見が得られた。このように、2021年度の研究により、本課題を進めるための基礎的知見が得られ、2022年度以降の実験計画を円滑に実行するための基盤を整備することができた。
  • 日本学術振興会：科学研究費助成事業 基盤研究(C)
    Date (from‐to) : 2020/04 -2023/03 
    Author : 関口 富美子; 川畑 篤史; 坪田 真帆
     
    本研究課題では、生体内で数種の合成酵素により産生される硫化水素（H2S）が、抗がん剤による化学療法誘起末梢神経障害（CIPN）の発症および抗がん剤抵抗性獲得に寄与するかを検討することを目的としている。実際に、抗がん剤によるCIPN発症と治療効果の減弱に内因性H2Sの寄与が明らかとなれば、H2S合成酵素阻害薬が抗がん剤との併用投与により、副作用であるCIPNの軽減と抗がん剤の治療効果増大の両面において高い有用性を示すことが期待できる。2020年度は、ヒト多発性骨髄腫（multiple myeloma, MM）由来KMS-11細胞と、MMの治療に使用される抗がん剤ボルテゾミブ（BTZ）に対して耐性を獲得したKMS-11/BTZ細胞を用いて、BTZ非存在下あるいは存在下における細胞増殖におよぼす内因性H2Sの関与について検討を行った。その結果、BTZ非存在下、存在下どちらにおいても、KMS-11およびKMS-11/BTZの細胞増殖はH2S合成酵素のcystathionine-β-synthase（CBS）の阻害薬により顕著に、cystathionine-γ-lyase（CSE）阻害薬により部分的に抑制されたが、CSE阻害薬の効果はKMS-11細胞で小さかった。これら阻害薬による増殖抑制効果はH2S供与体のNa2SあるいはGYY4137により一部減弱した。一方、別のH2S合成酵素である3-mercaptopyruvate sulfur transferase（3-MST）の阻害薬はこれら細胞の増殖にほとんど影響しなかった。これらの結果より、KMS-11およびKMS-11/BTZ細胞の増殖は内因性H2Sにより促進的に調節されており、その産生には主にCBSが寄与していることが示唆された。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2017/04 -2020/03 
    Author : Kawabata Atsufumi
     
    To develop seeds for development of medicines targeting RAGE for treatment of intractable pain, the present study first ascertained the involvement of RAGE in neuropathic and visceral pain using animal models. We then demonstrated that middle-molecular-weight-heparinylphenylalanine suppressed intractable pain possibly through selective blockade of RAGE. Our in silico analysis identified a small molecule compound that inhibits AGE-RAGE binding and is useful as a seed compound for novel RAGE blocker development. Together, our study identified both large and small molecules as RAGE blockers, which would be useful for pain treatment.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014/04 -2017/03 
    Author : SEKIGUCHI Fumiko
     
    Cav3.2 T-type calcium channels (T-channels) expressed in primary sensory neurons have been known to contribute to development of various intractable pain, including somatic, visceral and neuropathic pain. In the present study, we first examined analgesic effects of RQ-00311651, a novel T-channel blocker, in various pain model animals, and have reported that the compound may serve as an orally available analgesic for treatment of neuropathic and visceral pain with minimum central side effects. We also examined the mechanism of Cav3.2 upregulation in primary sensory neurons in a neuropathic pain model induced by L5 spinal nerve cutting, which we have reported previously, and have shown that increase in expression of Egr-1, a transcription factor, and USP5, a deubiquitinating enzyme, enhances transcription of Cav3.2 and suppresses proteasomal degradation of Cav3.2, respectively, leading to upregulation and maintenance of Cav3.2 expression in primary sensory neurons after nerve injury.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014/04 -2017/03 
    Author : KAWABATA Atsufumi
     
    HMGB1, a nuclear protein, is released into the extracellular space and plays a role as one of damage-associated molecular patterns in pathological conditions. Here we analyzed the role of HMGB1 in chemotherapy-induced neuropathic pain and visceral pain. Our data indicate that HMGB1 participates in the development and maintenance of chemotherapy-induced neuropathic pain and pancreatitis-related pain.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2011 -2013 
    Author : SEKIGUCHI Fumiko; KAWABATA Atsufumi
     
    In human gastric cancer-derived AGS cells, our findings suggest that endogenous hydrogen sulfide (H2S) produced by cystathionine-gamma-lyase (CSE), one of H2S-forming enzymes in the mammalian body, accelerates the proliferation of AGS cells. The effects of H2S may be mediated, in part, by increase in function of Cav3.2 T-type calcium channels and upregulation of anti-apoptotic proteins, Bcl-2 and Bcl-xL, via activation of NF-kappaB caused by endogenous H2S. These pathways can be expected to be effective targets for treatment of gastric cancer.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2011 -2013 
    Author : KAWABATA Atsufumi; SEKIGUCHI Fumiko; TSUBOTA Maho
     
    Among three isoforms of T-type calcium channels, Cav3.2 expressed abundantly in the peripheral ending of nociceptors plays a critical role in nociceptive processing. We thus examined molecular mechanisms for functional regulation of Cav3.2 by phosphorylation and dephosphorylation, and its impact on pain signals. Our data show that PKA, activated by stimulation of prostaglandin EP4 receptors in an AKAP150-dependent manner, phosphorylates and functionally upregulates Cav3.2, leading to hyperalgesia, and that calcineurin, a phosphatase, negatively regulates Cav3.2 functions.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2008 -2010 
    Author : SEKIGUCHI Fumiko; KAWABATA Atsufumi
     
    In the cancer area of gastric mucosal epithelium from gastric cancer patients, we found a tendency that expression of proteinase-activated receptor-1 (PAR1) was positively correlated with infection levels of Helicobacter pylori (H. pylori), suggesting involvement of increased expression of PAR1 in the development of H. pylori-related gastric cancer. We also determined if H. pylori might possess PAR-activating proteinases in various cell lines. However, we did not find any proteinases that activate PAR1, PAR2 or PAR4, in the H. pylori extracts.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2008 -2010 
    Author : KAWABATA Atsufumi; YOSHIDA Shigeru; SEKIGUCHI Fumiko
     
    We first demonstrated the involvement of Cav3.2 T-type calcium channels in hydrogen sulfide-induced facilitation of nociception. We then found that, in rats with L5 spinal nerve injury, the activation of Cav3.2 by endogenous hydrogen sulfide was involved in the maintenance of hyperalgesia/allodynia, and Cav3.2 was upregulated, suggesting that the hydrogen sulfide/Cav3.2 pathway should be a therapeutic target for treatment of neurogenic pain.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2005 -2007 
    Author : KAWABATA Atsufumi; SEKIGUCHI Fumiko; YOSHIDA Shigeru
     
    We investigated roles for hydrogen sulfide, a possible novel gasotransmitter, in nociceptive processing, and obtained the following results : 1) Hyperalgesia caused by administration of hydrogen sulfide and L-cysteine We first found that intraplantar (i.pl.) administration of NaHS, a donor for hydrogen sulfide, caused mechanical hyperalgesia in rats, an effect being mediated by activation of T-type calcium channels. Similarly, L-cysteine, an endogenous origin of hydrogen sulfide, when administered i.pl., produced hyperalgesia. This effect was considered to be mediated by production of endogenous hydrogen sulfide by cystathionine-gamma-lyase (CSE) from L-cysteine. The hyperalgesic effect of the hydrogen sulfide donor was accompanied by expression of Fos protein in the superficial layers of the spinal dorsal horn. 2) Facilitation by hydrogen sulfide of T-type calcium channel-mediated membrane currents in NG108-15 cells and mouse spinal dorsal root ganglion (DRG) neurons We examined effect of hydrogen sulfide on functions of T-type calcium channels by determining barium currents using the whole-cell-patch-clamp method, and found that hydrogen sulfide facilitated T-type calcium channel-mediated membrane currents on NG108-15 cells and mouse DRG neurons. 3) Visceral pain caused by colonic luminal hydrogen sulfide in mice Intracolonic administration of NaHS, a donor it hydrogen sulfide, caused visceral pain-like nociceptive behavior and referred abdominal hyperalgesia in mice, accompanied by phosphorylation of ERK in nociceptive neurons present in the superficial layers of the spinal dorsal horn. Together, our study strongly suggests that endogenous hydrogen sulfide plays a role as a novel messenger in nociceptive processing.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2001 -2003 
    Author : KAWABATA Atsufumi; KURODA Ryotaro
     
    The protease-activated receptor(PAR), a G protein-coupled receptor family consists of 4 members, and modulates a variety of physiological functions upon activation in response to inflammation, tissue injury and hemorrhage. The present study investigated the roles and changes of PARs, particularly PAR-2, in acute inflammation. We first studied changes of sensitivity of PAR-2 present in the salivary glands in mice treated with lipopolysaocharide, and found that PAR-2 might be tonically activated and desensitized by endogenous PAR-2 activators under systemic inflammatory conditions. Endogenous PAR activators including thrombin, factors VII and X, mast cell tryptase might become activated and/or accessible to tissues in septic shock. Vasodilation by these enzymes via PAR activation might contribute to development of hypotension caused by septic shock. In this context, we examined the mechanisms underlying the vascular contraction and relaxation caused by PAR activation. We then investigated roles of PARs, known to be present in capsaicin-sensitive sensory neurons, in inflammatory visceral pain and parotitis-related pain. Our data provide novel evidence that PARs, particularly PAR-2,is involved in inflammation and related pain, circulatory disturbance, etc.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2000 -2001 
    Author : KURODA Ryotaro; KAWABATA Atsufumi
     
    The aim of the study was to establish novel animal models in which electrical stimulation of cortical Sll area, known to be clinically analgesic, is capable of producing potent antinociception. 1. Sll stimulation-evoked antinociception in the formalin-induced nociception model : Stimulation electrodes were chronically implanted into the Sll area of the rat. The formalin-induced nociceptive behavior and expression of Fos in the superficial layer of the dorsal horn was slightly reduced by Sll stimulation. Sll stimulation in combination with 7-nitro indazole, a neuronal NO synthase inhibitor, produced strong antinociception and suppression of Fos expression. The effect of Sll stimulation was partially blocked by intrathecal administration of methysergide, a serotonin receptor antagonist, suggesting involvement of the descending serotonin neurons. 2. PAR-2-triggered nociception model and its characterization : Stimulation of PAR-2 expressed in the peripheral terminal of C-fiber triggered thermal hyperalgesia, nociceptive behavior and expression of spinal Fos. The nociceptive processing by PAR-2 was characterized in the present study. 3. Effect of Sll stimulation in the PAR-2-mediated nociception model and the surgically prepared neuropathy model : Sll stimulation failed to exhibit any antinociceptive activity in these two models. Further effort will be necessary to establish models in which Sll stimulation is highly analgesic.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 1999 -2000 
    Author : KAWABATA Atsufumi; KURODA Ryotaro
     
    Protease-activated receptors (PARs), G protein-coupled seven trans-membrane domain receptors activated by certain proteases such as thrombin, trypsin and tryptase, play various physiological/pathophysiological roles especially during tissue injury or inflammation. We investigated the physiological roles of PARs in the alimentary systems. Activation of PAR-1 produced apamin-sensitive relaxation followed by contraction in the isolated rat duodenal smooth muscle. PAR-2 activation elicited only contraction. PAR-4 produced no response. The PAR-1-mediated contraction was largely dependent on increased sodium permeability and activation of L-type calcium channels, and in part on activation of tyrosine kinase, protein kinase C and PI3 kinase. We next detected mRNA for PAR-2 in the salivary glands and pancreas. Then, activation of PAR-2 in vivo markedly augmented exocrine secretion in both the tissues. In conclusion, our study demonstrates that PARs present in the small intestine, salivary glands and pancreas modulate various physiological functions, predicting that PARs could be targets for drug development.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 1998 -1999 
    Author : KURODA Ryotaro; KAWABATA Atsufumi
     
    The primary aim of the present study was to establish an animal model in which analgesia could be produced by electrical stimulation of the secondary somatosensory cortex (S-II) that was clinically effective in a patient with intractable pain. We also wished to examine whether an inhibitor of neuronal nitric oxide (NO) synthase known to be involved in pain modulation could modify the S-II stimulation-produced analgesia. S-II stimulation failed to induce antinociception in rats, as assessed by mechanical and thermal nociception test. However, it produced notable antinociception in the formalin-induced chemical nociception test. This antinociception by S-II stimulation was potentiated by 7-nitro-indazole (7-NI), an inhibitor of neuronal NO synthase. S-II stimulation in combination with 7-NI also suppressed the formalin-induced expression of c-fos in the superficial layers of the L4 and L5 spinal dorsal horn. The antinociception evoked by S-II stimulation plus 7-NI was resistant to systemic administration of naloxone, an opioid antagonist, or of phentolamine, an α-adrenoceptor antagonist, whereas the first phase, but not second phase, antinociception was significantly inhibited by intrathecal administration of methysergide, a serotonin receptor antagonist. Our study suggests that S-II stimulation in combination with 7-NI produces strong antinociception by suppressing transmission of nociceptive information at a spinal level through activation of descending inhibitory pathways, especially serotonergic systems.
  • 日本学術振興会：科学研究費助成事業 奨励研究(A)
    Date (from‐to) : 1993 -1993 
    Author : 川畑 篤史
     
    1.脳内での疼痛制御におけるL‐arginineの役割 一酸化窒素(NO)は,L‐arginine(L‐Arg)からNO合成酵素(NOS)により生成され,soluble guanylate cyclase (sGC)を活性化して細胞内cyclic GMP(cGMP)濃度を上昇させることによりその生理作用を発現する.一方,内因性鎮痛ペプチドkyotorphin(L‐tyrosyl‐L‐arginine,以下KTP)は,脳内でKTP合成酵素(KTP‐S)によってL‐ArgとL‐tyrosineから生合成され,Met‐enkephalin(Met‐Enk)の遊離を促進させることにより生理作用を発現する.著者らはL‐ArgがNOSおよびKTP‐Sの両酵素の基質である点に注目し,脳内での疼痛制御における役割を検討した.L‐Arg,NOS阻害薬およびsGC阻害薬はいずれも側脳室内投与により明らかな抗侵害作用を示した.L‐Argのこの効果はKTP‐Met‐Enk経路を促進することにより発現するのに対し,NOS阻害薬およびsGC阻害薬の効果はNO‐cGMP経路を抑制することにより発現することが明らかとなった.このことより,L‐Argは脳内で相反する2つの役割,すなわち,KTP系を介する抗侵害的な面とNO系を介する侵害的な面を有することが強く示唆された. 2.末梢での侵害受容におけるL‐arginineの役割 炎症時の侵害受容において,末梢組織中のNOが血管透過性を亢進させることにより侵害受容を促進させるとの見解と,nociceptorへの直接的な抑制作用により抗侵害的に作用するとの見解が対立した現状にある.著者らは,formalin誘発侵害反応モデルを用いてこの矛盾点の解明を試みた.その結果,末梢組織中でL‐Argより生成されるNOはその濃度に依存して侵害促進的な面と侵害抑制的な面を合わせ持つことが示唆された.
  • プロテアーゼ受容体に関する研究
  • 疼痛制御メカニズムに関する研究
  • Study on protease-activated receptors
  • Study on pain modulation systems.

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