坪田 真帆 (ツボタ マホ)

  • 薬学部 医療薬学科 講師
Last Updated :2024/02/01

コミュニケーション情報 byコメンテータガイド

  • コメント

    内臓痛に関わる分子について研究しています。内臓痛の発現メカニズムは非常に複雑で未解明な点が数多く残されています。発現メカニズムを解明し、新たな治療法を確立することを目指しています。

研究者情報

学位

  • 博士(薬学)(近畿大学)

ホームページURL

J-Global ID

研究キーワード

  • 膀胱痛   痛み   硫化水素   サブスタンスP   炎症   内因性ガス   T型Ca^<2+>チャネル   ガスメッセンジャー   膀胱炎   膀胱炎症   硫化水素合成酵素   一次知覚神経   神経因性炎症   プロテインキナーゼA   神経突起   イオンチャネル   カルシニューリン   薬理学   カルシウムチャネル   神経突起伸長   カルシウム   疼痛制御   PKA   Cav3.2   

現在の研究分野(キーワード)

    内臓痛に関わる分子について研究しています。内臓痛の発現メカニズムは非常に複雑で未解明な点が数多く残されています。発現メカニズムを解明し、新たな治療法を確立することを目指しています。

研究分野

  • ライフサイエンス / 薬理学
  • ライフサイエンス / 病態神経科学

経歴

  • 2018年04月 - 現在  近畿大学薬学部 医療薬学科講師
  • 2013年04月 - 2018年03月  近畿大学薬学部 医療薬学科助教
  • 2008年04月 - 2013年03月  近畿大学薬学部 医療薬学科助手

研究活動情報

論文

  • 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 14 1 2024年01月 
    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.
  • 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年06月 
    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年02月 
    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年01月 
    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年 
    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年08月 
    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 148 3 315 - 325 2022年03月 
    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年01月 
    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.
  • Maho Tsubota; Takaya Miyazaki; Yuya Ikeda; Yusuke Hayashi; Yui Aokiba; Shiori Tomita; Fumiko Sekiguchi; Dengli Wang; Masahiro Nishibori; Atsufumi Kawabata
    Cells 10 10 2021年09月 
    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年07月 
    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年05月 
    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.
  • 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年02月
  • Maho Tsubota; Kazuki Matsui; Saaya Fukushi; Kyoko Okazaki; Fumiko Sekiguchi; Atsufumi Kawabata
    Biological & pharmaceutical bulletin 44 3 461 - 464 2021年 
    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.
  • Shiori Tomita; Fumiko Sekiguchi; Yoshihito Kasanami; Katsuki Naoe; Maho Tsubota; Hidenori Wake; Masahiro Nishibori; Atsufumi Kawabata
    European journal of pharmacology 888 173587 - 173587 2020年12月 
    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.
  • 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年11月 
    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.
  • 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年07月 [査読有り]
     
    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年06月 [査読有り]
     
    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年05月 [査読有り]
     
    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.
  • Kazuki Matsui; Yuka Terada; Maho Tsubota; Fumiko Sekiguchi; Atsufumi Kawabata
    Journal of pharmacological sciences 143 1 60 - 63 2020年05月 [査読有り]
     
    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.
  • 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年10月 [査読有り]
     
    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.
  • Matsui K; Tsubota M; Fukushi S; Koike N; Masuda H; Kasanami Y; Miyazaki T; Sekiguchi F; Ohkubo T; Yoshida S; Mukai Y; Oita A; Takada M; Kawabata A
    Journal of pharmacological sciences 140 3 310 - 312 2019年07月 [査読有り]
     
    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 2019年06月 [査読有り]
     
    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.
  • Maho Tsubota; Kenta Uebo; Koki Miki; Fumiko Sekiguchi; Akihiko Ishigami; Atsufumi Kawabata
    Biochemical and biophysical research communications 511 3 705 - 710 2019年04月 [査読有り]
     
    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 2019年02月 [査読有り]
     
    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.
  • Maho Tsubota; Atsufumi Kawabata
    PAIN RESEARCH 34 1 24 - 30 2019年 
    Accumulating evidence sheds light on the crucial role of a neuroimmune crosstalk in neurogenic inflammation and diverse neurological diseases associated with neuroinflammation. High mobility group box 1 (HMGB1), one of damage-associated molecular patterns (DAMPs)/alarmins, is now considered a pro-inflammatory/pronociceptive molecule, and participates in the pathogenesis of neuropathic and inflammatory pain. In this review, we focus on the role of HMGB1 in visceral pain signaling in the bladder, pancreas and colon. In rodent models for cystitis-related bladder pain, macrophage-derived HMGB1 activates the receptor for advanced glycation end-products (RAGE), and induces NF-kappa B-dependent overexpression of cystathionine-gamma-lyase, an H2S-generating enzyme, resulting in excessive excitation of nociceptors through the H2S/Ca(v)3.2 T-type calcium channel pathway and subsequent bladder pain. The macrophage-derived HMGB1 also appears to play a role in the development of pancreatic pain accompanying acute pancreatitis and of colonic pain in a mouse model for irritable bowel syndrome (IBS). Thus, HMGB1 is considered a key mediator for a neuroimmune crosstalk involved in visceral pain signaling in the bladder, pancreas and colon, and may serve as a novel therapeutic target for treatment of visceral pain in patients with interstitial cystitis/bladder pain syndrome, acute pancreatitis or IBS.
  • 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年 [招待有り]
  • 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年 [査読有り]
  • 坪田真帆; 川畑篤史
    日本薬理学雑誌 154 3 128 - 132 2019年 [査読有り]
     
    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.
  • 川畑篤史; 坪田真帆; 関口富美子; 辻田隆一; 辻田隆一
    日本薬理学雑誌 154 5 236 - 240 2019年 [査読有り]
     
    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 2018年10月 [査読有り]
     
    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 2018年08月 [査読有り]
     
    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 2018年08月 [査読有り]
     
    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 2018年06月 [査読有り]
     
    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.
  • Tsubota M; Okawa Y; Irie Y; Maeda M; Ozaki T; Sekiguchi F; Ishikura H; Kawabata A
    Neuropharmacology 133 254 - 263 2018年05月 [査読有り]
     
    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.
  • Ozaki T; Tsubota M; Sekiguchi F; Kawabata A
    Clinical and experimental pharmacology & physiology 45 4 355 - 361 2018年04月 [査読有り]
     
    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 2018年01月 [査読有り]
     
    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.
  • Yusuke Hayashi; Ryuichi Tsujita; Maho Tsubota; Haruka Saeki; Fumiko Sekiguchi; Goichi Honda; Atsufumi Kawabata
    Biochemical and biophysical research communications 495 1 634 - 638 2018年01月 [査読有り]
     
    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 2018年01月 [査読有り]
     
    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.
  • Fumiko Sekiguchi; Maho Tsubota; Atsufumi Kawabata
    Biological & pharmaceutical bulletin 41 8 1127 - 1134 2018年 [査読有り]
     
    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.
  • Yuhei Irie; Maho Tsubota; Hiroyasu Ishikura; Fumiko Sekiguchi; Yuka Terada; Toshifumi Tsujiuchi; Keyue Liu; Masahiro Nishibori; Atsufumi Kawabata
    JOURNAL OF NEUROIMMUNE PHARMACOLOGY 12 4 693 - 707 2017年12月 [査読有り]
     
    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.
  • Maho Tsubota; Ryotaro Fukuda; Fumiko Sekiguchi; Takaya Miyazaki; Risa Domoto; Hiroki Yasui; Takeshi Nishida; Hiroyasu Ishikura; Masahiro Nishibori; Atsufumi Kawabata
    JOURNAL OF PHARMACOLOGICAL SCIENCES 133 3 S97 - S97 2017年03月
  • Tomoyoshi Miyamoto; Yoshinori Funakami; Erika Kawashita; Shiori Tomita; Ai Nomura; Nanako Sugimoto; Haruka Saeki; Takaya Miyazaki; Maho Tsubota; Seiji Ichida; Atsufumi Kawabata
    PHARMACOLOGY 99 3-4 172 - 178 2017年 [査読有り]
     
    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 40 1 11 - 16 2017年01月 [査読有り]
     
    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.
  • Yuka Terada; Maho Tsubota; Hiiragi Sugo; Kohei Wakitani; Fumiko Sekiguchi; Kyoichi Wada; Mitsutaka Takada; Akira Oita; Atsufumi Kawabata
    PHARMACOLOGY 99 5-6 281 - 285 2017年 [査読有り]
     
    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 99 5-6 286 - 290 2017年 [査読有り]
     
    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 157 8 1655 - 1665 2016年08月 [査読有り]
     
    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.
  • Takeshi Nishida; Maho Tsubota; Yudai Kawaishi; Hiroki Yamanishi; Natsuki Kamitani; Fumiko Sekiguchi; Hiroyasu Ishikura; Keyue Liu; Masahiro Nishibori; Atsufumi Kawabata
    TOXICOLOGY 365 48 - 58 2016年07月 [査読有り]
     
    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.
  • 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 130 3 S146 - S146 2016年03月 [査読有り]
  • Irie Yuhei; Tsubota Maho; Sekiguchi Fumiko; Ishikura Hiroyasu; Nishibori Masahiro; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES 130 3 S81  2016年03月 [査読有り]
  • Tomita Shiori; Shikimi Shiyu; Sekiguchi Fumiko; Tsubota Maho; Shirai Akihiro; Nishibori Masahiro; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES 130 3 S82  2016年03月 [査読有り]
  • Matsuoka Junki; Ozaki Tomoka; Tsubota Maho; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES 130 3 S200  2016年03月 [査読有り]
  • Tsubota Maho; Yamasoba Daichi; Domoto Risa; Sekiguchi Fumiko; Nishibori Masahiro; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES 130 3 S235 - S235 2016年03月 [査読有り]
  • Maeda Mariko; Irie Yuhei; Tsubota Maho; Kubo Lisa; Sekiguchi Fumiko; Ishikura Hiroyasu; Nishibori Masahiro; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES 130 3 S144  2016年03月 [査読有り]
  • 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 130 2 139 - 142 2016年02月 [査読有り]
     
    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 130 1 38 - 41 2016年01月 [査読有り]
     
    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.
  • Tsubota Maho; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES 128 3 S40 - S40 2015年07月 [査読有り]
  • Hiruma Saki; Murakami; Nakayama) Masahiro; Tsubota Maho; Sekiguchi Fumiko; Matsuyama Kenji; Kimura Takeshi; Moriyama Masahiro; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES 128 3 S110  2015年07月 [査読有り]
  • Yamasoba Daichi; Seki Yukari; Yamanishi Hiroki; Tsubota Maho; Sekiguchi Fumiko; Yagi Hideki; Masuko Takashi; Nishibori Masahiro; Kawabata Atsufumi
    JOURNAL OF PHARMACOLOGICAL SCIENCES 128 3 S104 - S104 2015年07月 [査読有り]
  • 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 135年会 1 333 - 333 (公社)日本薬学会 2015年03月
  • Yuka Terada; Mayuko Fujimura; Sachiyo Nishimura; Maho Tsubota; Fumiko Sekiguchi; Atsufumi Kawabata
    JOURNAL OF NEUROSCIENCE RESEARCH 93 2 361 - 369 2015年02月 [査読有り]
     
    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 127 2 223 - 228 2015年02月 [査読有り]
     
    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.
  • Maho Tsubota; Atsufumi Kawabata
    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 134 12 1245 - 1252 2014年12月 [査読有り]
     
    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 79 112 - 118 2014年04月 [査読有り]
     
    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.
  • 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 2013年11月 [査読有り]
     
    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 123 3 284 - 287 2013年11月 [査読有り]
     
    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 36 8 1278 - 1282 2013年08月 [査読有り]
     
    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; Yuka Aoki; Maiko Nakagawa; Daiki Kanaoka; Yuta Nishimoto; Maho Tsubota-Matsunami; Rumi Yamanaka; Shigeru Yoshida; Atsufumi Kawabata
    BRITISH JOURNAL OF PHARMACOLOGY 168 3 734 - 745 2013年02月 [査読有り]
     
    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 2013年 [査読有り]
     
    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.
  • 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 140 4 3P - 3P (公社)日本薬理学会 2012年10月
  • 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 167 4 917 - 928 2012年10月 [査読有り]
     
    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 166 5 1738 - 1743 2012年07月 [査読有り]
     
    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 119 3 293 - 296 2012年07月 [査読有り]
     
    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 166 3 1058 - 1068 2012年06月 [査読有り]
     
    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 63 1 61 - 68 2012年02月 [査読有り]
     
    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 30 212 - 218 2012年 [査読有り]
     
    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
  • K. Okubo; T. Takahashi; F. Sekiguchi; D. Kanaoka; M. Matsunami; T. Ohkubo; J. Yamazaki; N. Fukushima; S. Yoshida; A. Kawabata
    Neuroscience 188 148 - 156 2011年08月 
    Hydrogen sulfide (H2S), a gasotransmitter, facilitates pain sensation by targeting Cav3.2 T-type calcium channels. The H2S/Cav3.2 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-γ-lyase (CSE), a major H2S-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 Cav3.1, and mibefradil inhibited T-type currents in Cav3.2-transfected HEK293 cells. Repeated systemic administration of paclitaxel caused delayed development of mechanical hyperalgesia, which was reversed by single intraplantar administration of NNC 55-0396 or mibefradil, and by silencing of Cav3.2 by antisense oligodeoxynucleotides. Systemic administration of dl-propargylglycine and β-cyanoalanine, irreversible and reversible inhibitors of CSE, respectively, also abolished the established neuropathic hyperalgesia. In the paclitaxel-treated rats, upregulation of Cav3.2 and CSE at protein levels was not detected in the dorsal root ganglia (DRG), spinal cord or peripheral tissues including the hindpaws, whereas H2S content in hindpaw tissues was significantly elevated. Together, our study demonstrates the effectiveness of NNC 55-0396 in inhibiting Cav3.2, 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 Cav3.2 and CSE at protein levels, differing from the previous evidence for the neuropathic pain model induced by spinal nerve cutting in which Cav3.2 was dramatically upregulated in DRG. © 2011 IBRO.
  • Takahiro Miki; Maho Matsunami; Saori Nakamura; Hiroki Okada; Hidekazu Matsuya; Atsufumi Kawabata
    PAIN 152 6 1373 - 1381 2011年06月 [査読有り]
     
    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 181 257 - 264 2011年05月 [査読有り]
     
    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.
  • Osamu Fukushima; Sachiyo Nishimura; Maho Matsunami; Yuka Aoki; Hiroyuki Nishikawa; Hiroyasu Ishikura; Atsufumi Kawabata
    JOURNAL OF NEUROSCIENCE RESEARCH 88 14 3198 - 3205 2010年11月 [査読有り]
     
    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 87 19-22 643 - 650 2010年11月 [査読有り]
     
    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.
  • Eiichi Taniguchi; Maho Matsunami; Takeshi Kimura; Daiki Yonezawa; Tsuyoshi Ishiki; Fumiko Sekiguchi; Hiroyuki Nishikawa; Yuma Maeda; Hiroyasu Ishikura; Atsufumi Kawabata
    TOXICOLOGY 264 1-2 96 - 103 2009年10月 [査読有り]
     
    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.
  • M. Matsunami; T. Tarui; K. Mitani; K. Nagasawa; O. Fukushima; K. Okubo; S. Yoshida; M. Takemura; A. Kawabata
    GUT 58 6 751 - 761 2009年06月 [査読有り]
     
    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.
  • S. Nishimura; O. Fukushima; H. Ishikura; T. Takahashi; M. Matsunami; T. Tsujiuchi; F. Sekiguchi; M. Naruse; Y. Kamanaka; A. Kawabata
    GUT 58 6 762 - 770 2009年06月 [査読有り]
     
    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.
  • Yumi Maeda; Yuka Aoki; Fumiko Sekiguchi; Maho Matsunami; Tomoko Takahashi; Hiroyuki Nishikawa; Atsufumi Kawabata
    PAIN 142 1-2 127 - 132 2009年03月 [査読有り]
     
    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 108 3 676 - 684 2009年02月 [査読有り]
     
    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.
  • A. Kawabata; M. Matsunami; F. Sekiguchi
    BRITISH JOURNAL OF PHARMACOLOGY 153 S230 - S240 2008年03月 [査読有り]
     
    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.
  • Hiroyasu Ishikura; Sachiyo Nishimura; Maho Matsunami; Toshifumi Tsujiuchi; Tsuyoshi Ishiki; Fumiko Sekiguchi; Mitsuhide Naruse; Toshio Nakatani; Yoshihisa Kamanaka; Atsufumi Kawabata
    LIFE SCIENCES 80 21 1999 - 2004 2007年05月 [査読有り]
     
    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.
  • Matsunami M; Sekiguchi T; Kawabata A
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica 128 6 434 - 436 2006年12月 [査読有り]
  • Atsufumi Kawabata; Naoyuki Kawao; Yoshimi Hironaka; Tsuyoshi Ishiki; Maho Matsunami; Fumiko Sekiguchi
    NEUROPHARMACOLOGY 51 2 182 - 190 2006年08月 [査読有り]
     
    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.
  • A Kawabata; N Kawao; T Kitano; M Matsunami; R Satoh; T Ishiki; T Masuko; T Kanke; N Saito
    NEUROSCIENCE LETTERS 402 1-2 167 - 172 2006年07月 [査読有り]
     
    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 148 1 54 - 60 2006年05月 [査読有り]
     
    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.
  • Kubozoe T; Tsutsumi M; Murata N; Tsujiuchi T; Tsubota M; Sugimura T; Wakabayashi K; Konishi Y
    J Toxicol Pathol 15 1 7 - 12 2002年 [査読有り]
  • Kubozoe T; Tsujiuchi T; Murata N; Sasaki Y; Tsubota M; Konishi Y; Tsutsumi M
    Cancer Lett. 168 1 - 6 2001年 [査読有り]
  • K Iki; T Tsujiuchi; T Majima; H Sakitani; M Tsutsumi; M Takahama; M Yoshimoto; D Nakae; M Tsubota; Y Konishi
    CANCER LETTERS 131 2 185 - 190 1998年09月 [査読有り]
     
    Telomerase activities in intrahepatic cholangiocarcinomas induced by N-nitrosobis (2-oxopropyl)amine (BOP) in female hamsters were determined using a telomeric repeat amplification protocol (TRAP) assay followed by densitometric quantification. Each determination was repeated to confirm the results and telomerase activity was also detected by gel electrophoresis. An increase was evident in all of 10 cholangiocarcinomas examined, with levels ranging from 2.48 to 4.40 times the normal liver value by densitometric quantification. This finding of a consistent increase suggests that telomerase activation is involved in the development of intrahepatic cholangiocarcinomas and immortalization of cancer cells. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.

講演・口頭発表等

  • Butyrate誘起結腸過敏への補体C5aの関与
    西村彩花、山縣歩夢、坪田真帆、川畑篤史
    第72回 日本薬学会関西支部総会・大会 2022年10月 ポスター発表 枚方
  • 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 ポスター発表
  • 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 ポスター発表
  • 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年07月 口頭発表(一般)
  • 香族L-アミノ酸脱炭酸酵素を阻害しないD-carbidopaはH2S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  [通常講演]
    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
    第141回日本薬理学会近畿部会 2022年07月 口頭発表(一般)
  • 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 口頭発表(一般)
  • 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 口頭発表(一般)
  • 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 口頭発表(一般)
  • 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 口頭発表(一般)
  • 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 口頭発表(一般)
  • 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 口頭発表(一般)
  • 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 ポスター発表
  • 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年01月 口頭発表(一般)
  • 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年11月 口頭発表(一般)
  • 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年11月 口頭発表(一般)
  • 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―  [招待講演]
    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年10月 口頭発表(招待・特別) 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  [通常講演]
    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年10月 ポスター発表 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  [通常講演]
    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年10月 ポスター発表 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  [通常講演]
    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年10月 ポスター発表 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  [通常講演]
    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年10月 ポスター発表 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  [通常講演]
    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年10月 ポスター発表 東大阪
  • Cav3.2 T型Ca2+チャネルおよびHMGB1の役割  [通常講演]
    坪田真帆、川畑篤史
    生体機能と創薬シンポジウム2021 2021年08月 口頭発表(一般) 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  [通常講演]
    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年08月 ポスター発表 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  [通常講演]
    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年08月 ポスター発表 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  [通常講演]
    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年08月 ポスター発表 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  [通常講演]
    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年06月 口頭発表(一般) 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  [通常講演]
    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年06月 口頭発表(一般) 名古屋(リモート)
  • 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  [通常講演]
    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 ポスター発表 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  [通常講演]
    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 ポスター発表 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  [通常講演]
    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 口頭発表(一般) 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  [通常講演]
    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 口頭発表(一般) 札幌 (ハイフレックス)
  • 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  [通常講演]
    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年11月 口頭発表(一般) 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  [通常講演]
    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年11月 口頭発表(一般) 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  [通常講演]
    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年11月 シンポジウム・ワークショップパネル(指名) 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  [通常講演]
    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年10月 口頭発表(一般) 草津(リモート)
  • Middle molecular weight heparinylphenylalanine selectively blocks RAGE and reduces HMGB1-dependent neuropathic and visceral pain in mice  [通常講演]
    Kawabata, A., Nishikawa, H. Higashimoto, K., Uenoyama, K., Sekiguchi, F., Tsubota, M., Okada, T., Toyooka, N
    12th FENS Forum of Neuroscience ポスター発表 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  [通常講演]
    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 ポスター発表 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  [通常講演]
    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 ポスター発表 横浜(リモート)
  • Hepatic injury aggravates oxaliplatin-induced peripheral neuropathy in mice: possible involvement of HMGB1 derived from the liver.  [通常講演]
    Kamaguchi, R., Domoto, R., Sekiguchi, F., Tsubota, M., Nishibori, M., Kawabata, A.
    “Pain and Survival Strategy”, National Institute of Physiological Sciences International Workshop on Frontiers in Defensive Survival Circuit Research(痛み研究会2019) ポスター発表 岡崎
  • 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  [通常講演]
    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年11月 口頭発表(一般) 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  [通常講演]
    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年11月 口頭発表(一般) 枚方
  • Involvement of HMGB1 in bortezomib-induced peripheral neuropathy in mice.  [通常講演]
    Ikeda, Y., Miyazak, T., Tsubota, M., Tomita, S., Sekiguchi, F., Nishibori, M., Kawabata, A.
    The 6th Asian College of Neuropsychopharmacology (AsCNP) Congress ポスター発表 福岡
  • Endogenous thrombin plays a preventive role against oxaliplatin-induced peripheral neuropathy: involvement of thrombomodulin-dependent inactivation of HMGB1 by thrombin.  [通常講演]
    Tsubota, M., Fukuda, R., Hayashi, Y., Miyazaki, T., Ueda, S., Nishibori, M., Kawabata, A.
    The 6th Asian College of Neuropsychopharmacology (AsCNP) Congress ポスター発表 福岡
  • 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  [通常講演]
    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年10月 ポスター発表 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  [通常講演]
    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年10月 ポスター発表 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.  [通常講演]
    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年10月 ポスター発表 神戸
  • Crosstalk between the HMGB1/RAGE and CSE/H2S/Cav3.2 pathways involved in cystitis-related bladder pain in mice.  [通常講演]
    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年09月 ポスター発表 Valencia, Spain
  • Hepatic injury aggravates oxaliplatin-induced peripheral neuropathy in mice: possible involvement of HMGB1.  [通常講演]
    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年09月 ポスター発表 Valencia, Spain
  • Critical role of Cav3.2 T-type calcium channels in H2S-dependent somatic and visceral pain signaling in mice.  [通常講演]
    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年09月 ポスター発表 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.  [通常講演]
    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年09月 ポスター発表 Valencia, Spain
  • Dietary ascorbic acid restriction in GNL/SMP30-knockout mice unveils the role of ascorbic acid in regulation of Cav3.2-dependent pain.  [通常講演]
    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年09月 ポスター発表 Valencia, Spain
  • 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.  [通常講演]
    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年08月 口頭発表(一般) 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.  [通常講演]
    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年08月 ポスター発表 東京
  • 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.  [通常講演]
    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年06月 口頭発表(一般) 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.  [通常講演]
    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年06月 口頭発表(一般) 岐阜
  • 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.  [通常講演]
    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年03月 ポスター発表 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  [通常講演]
    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年03月 ポスター発表 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.  [通常講演]
    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年03月 ポスター発表 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.  [通常講演]
    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年03月 ポスター発表 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.  [通常講演]
    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年03月 口頭発表(一般) 大阪
  • 硫化水素によるCav3.2を介する疼痛シグナルの調節.  [通常講演]
    坪田真帆; 川畑篤史
    第92回日本薬理学会年会 2019年03月 シンポジウム・ワークショップパネル(公募) 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  [通常講演]
    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年12月 ポスター発表 岡崎
  • 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.  [通常講演]
    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年11月 口頭発表(一般) 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.  [通常講演]
    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年11月 口頭発表(一般) 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.  [通常講演]
    坪田真帆; 川畑篤史
    第91回日本生化学会大会 2018年09月 シンポジウム・ワークショップパネル(公募) 京都
  • Azelastine attenuates RAGE-dependent allodynia in mice: a discovery by a drug reprofiling/repositioning approach.  [通常講演]
    Wakitani, K; Sekiguchi, F; Tsubota, M; Nakamura, S; Nakanishi, I; Kawabata, A
    17th World Congress on Pain. 2018年09月 ポスター発表 Boston, USA
  • Pharmacological blockade and genetic deletion of Cav3.2 T-type Ca2+ channels abolish butyrate-induced colonic hypersensitivity in mice.  [通常講演]
    Matsui, K; Nakano, M; Tomochika, K; Tsubota, M; Kawabata, A
    17th World Congress on Pain. 2018年09月 ポスター発表 Boston, USA
  • Middle Molecular Weight Heparinylphenylalanine Prevents the Development of Chemotherapy-Induced Peripheral Neuropathy in Mice.  [通常講演]
    Kawabata, A; Nishikawa, H; Uenoyama, K; Sekiguchi, F; Tsubota, M; Okada, T; Toyooka, N
    17th World Congress on Pain. 2018年09月 ポスター発表 Boston, USA
  • 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.  [通常講演]
    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年08月 ポスター発表 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  [通常講演]
    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年08月 ポスター発表 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  [通常講演]
    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年08月 ポスター発表 福岡
  • Effect of extracellular HMGB1 on neuritogenesis in mouse dorsal root ganglion neurons and its inhibition by thrombomodulin alfa.  [通常講演]
    Nakatake, Y; Sekiguchi, F; Tsubota, M; Tsujita, R; Honda, G; Kawabata, A
    11thFENS Forum of Neuroscience. 2018年07月 ポスター発表 Berlin, Germany
  • ATP and HMGB1 mediate H2S-dependent bladder pain in mice with cyclophosphamide-induced cystitis.  [通常講演]
    Hiramoto, S; Tsubota, M; Yamaguchi, K; Toriyama, Y; Tanaka, J; Sekiguchi, F; Ishikura, H; Nishibori, M; Kawabata, A
    11thFENS Forum of Neuroscience. 2018年07月 ポスター発表 Berlin, Germany
  • Molecular mechanisms for the HMGB1-dependent mechanical allodynia following intraplantar administration of lipopolysaccharidein mice.  [通常講演]
    Domoto, R; Yamasoba, D; Sekiguchi, F; Tsubota, M; Nishibori, M; Kawabata, A
    11thFENS Forum of Neuroscience. 2018年07月 ポスター発表 Berlin, Germany
  • Cav3.2 T-type calcium channels as therapeutic targets for bortezomib-induced peripheral neuropathy in mice.  [通常講演]
    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年07月 ポスター発表 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.  [通常講演]
    Hayashi, Y; Tsubota, M; Tsujita, R; Honda, G; Kawabata, A
    18th World Congress of Basic and Clinical Pharmacology 2018年07月 ポスター発表 Kyoto, Japan
  • Macrophage-derived HMGB1 is a key molecule in paclitaxel-induced peripheral neuropathy in mice: involvement of ROS generation and NF-κB activation.  [通常講演]
    Domoto, R; Yamasoba, D; Yamanishi, H; Sekiguchi, F; Tsubota, M; Nishibori, M; Kawabata, A
    18th World Congress of Basic and Clinical Pharmacology 2018年07月 口頭発表(一般) Kyoto, Japan
  • Middle molecular weight heparinylphenylalanine is an analgesic with reduced risk of hemorrhage.  [通常講演]
    Nishikawa, H; Uenoyama, K; Sekiguchi, F; Tsubota, M; Kawabata, A
    18th World Congress of Basic and Clinical Pharmacology 2018年07月 ポスター発表 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  [通常講演]
    Tsubota, M; Matsui, K; Nakano; M. Tomochika, K; Sekiguchi, F; Kawabata, A
    10th International Symposium on Cell/Tissue Injury and Cytoprotection/Organoprotection. 2018年06月 ポスター発表 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  [通常講演]
    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年06月 ポスター発表 長崎
  • 急性および慢性術後痛におけるHMGB1の役割  [通常講演]
    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年06月 口頭発表(一般) 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  [通常講演]
    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年06月 口頭発表(一般) 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  [通常講演]
    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年06月 口頭発表(一般) 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  [通常講演]
    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年06月 口頭発表(一般) 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  [通常講演]
    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年06月 口頭発表(一般) 広島
  • 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  [通常講演]
    辻田隆一; 坪田真帆; 林佑亮; 佐伯晴香; 本田剛一; 川畑篤史
    痛み研究会2017(痛みを中心とする有害状況適応の神経戦略バイオロジー) 2017年12月 口頭発表(一般) 名古屋
  • 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  [通常講演]
    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年11月 口頭発表(一般) 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  [通常講演]
    坪田真帆; 川畑篤史
    第45回日本潰瘍学会 2017年11月 口頭発表(一般) 京都
  • Involvement of HMGB1 in postoperative pain.  [通常講演]
    Kawabata, Y; Tsubota, M; Tsujita, R; Nishibori, M; Kawabata, A
    Neuroscience 2017 2017年11月 ポスター発表 Washington DC, USA
  • Thrombin-dependent inhibition of HMGB1-induced mechanical allodynia by thrombomodulin in mice.  [通常講演]
    Hayashi, Y; Tsubota, M; Tsujita, R; Honda, G; Kawabata, A
    Neuroscience 2017 2017年11月 ポスター発表 Washington DC, USA
  • HMGB1-induced neurite outgrowth in mouse dorsal root ganglion neurons and its inhibition by thrombomodulin  [通常講演]
    Nakatake, Y; Sekiguchi, F; Tsubota, M; Tsujita, R; Honda, G; Kawabata, A
    Neuroscience 2017 2017年11月 ポスター発表 Washington DC, USA
  • Macrophages and NF-κB signaling mediate peripheral HMGB1-induced mechanical allodynia in mice.  [通常講演]
    Domoto, R; Nakashima, K; Tsubota, M; Sekiguchi, F; Kawabata, A
    Neuroscience 2017 2017年11月 ポスター発表 Washington DC, USA
  • Tacrolimus, a calcineurin inhibitor, promotes capsaicin-induced colonic pain in mice  [通常講演]
    Matsui, K; Terada, Y; Tsubota, M; Kawabata, A
    Neuroscience 2017 2017年11月 ポスター発表 Washington DC, USA
  • Involvement of Cav3.2 T-type calcium channels in zinc deficiency-induced mechanical allodynia in mice.  [通常講演]
    Sekiguchi, F; Tomita, S; Shikimi, S; Tsubota, M; Kawabata, A
    Neuroscience 2017 2017年11月 ポスター発表 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.  [通常講演]
    Kawabata, A; Tomita, S; Deguchi, T; Sekiguchi, F; Tsubota, M; Yoshida, S
    Neuroscience 2017 2017年11月 ポスター発表 Washington DC, USA
  • Design and synthesis of novel anti-hyperalgesic agents based on 6-prenylnaringen as the T-type calcium channel blockers  [通常講演]
    Nguyen, H.D; Okada, T; Kitamura, S; Yamaoka, S; Horaguchi, Y; Kasanami, Y; Sekiguchi, F; Tsubota, M; Yoshida, S; Kawabata, A; Toyooka, N
    第35回メディシナルケミストリーシンポジウム 2017年10月 ポスター発表 名古屋
  • 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―  [通常講演]
    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年10月 口頭発表(一般) 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.  [通常講演]
    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年09月 ポスター発表 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  [通常講演]
    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年08月 口頭発表(一般) 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  [通常講演]
    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年08月 口頭発表(一般) 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  [通常講演]
    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年08月 口頭発表(一般) 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.  [通常講演]
    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年08月 ポスター発表 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.  [通常講演]
    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年08月 ポスター発表 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.  [通常講演]
    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年08月 ポスター発表 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.  [通常講演]
    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年08月 ポスター発表 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.  [通常講演]
    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年08月 ポスター発表 京都
  • 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  [通常講演]
    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年07月 ポスター発表 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  [通常講演]
    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年06月 口頭発表(一般) 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.  [通常講演]
    中島夏奈; 堂本莉紗; 関口富美子; 坪田真帆; 川畑篤史
    2017年06月 口頭発表(一般) 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.  [通常講演]
    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年06月 口頭発表(一般) 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  [通常講演]
    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年06月 ポスター発表 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.  [通常講演]
    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年06月 ポスター発表 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.  [通常講演]
    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年06月 口頭発表(一般) 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.  [通常講演]
    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年06月 口頭発表(一般) 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.  [通常講演]
    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90回日本薬理学会年会 2017年03月 ポスター発表 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.  [通常講演]
    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年03月 ポスター発表 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.  [通常講演]
    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年03月 ポスター発表 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.  [通常講演]
    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年03月 口頭発表(一般) 長崎
  • HMGB1は術後痛に関与する.  [通常講演]
    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年03月 口頭発表(一般) 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.  [通常講演]
    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年03月 口頭発表(一般) 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  [通常講演]
    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年03月 口頭発表(一般) 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  [通常講演]
    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年01月 口頭発表(一般) 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.  [通常講演]
    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年01月 口頭発表(一般) 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.  [通常講演]
    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年11月 口頭発表(一般) 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.  [通常講演]
    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年11月 口頭発表(一般) 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.  [通常講演]
    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年11月 ポスター発表 京都
  • A role of macrophage-derived HMGB1 in paclitaxel-induced peripheral neuropathy in mice.  [通常講演]
    Domoto, R; Yamasoba, D; Yamanishi, H; Sekiguchi, F; Tsubota, M; Nishibori, M; Kawabata, A
    The 12th International Conference on Protein Phosphatase 2016年10月 ポスター発表 Higashi-Osaka, Japan
  • Cav3.2 T-type calcium channels as therapeutic targets for the oxaliplatin-induced peripheral neuropathy.  [通常講演]
    Miyazaki, T; Fukuda, R; Tsubota, M; Kawabata, A
    The 12th International Conference on Protein Phosphatase 2016年10月 ポスター発表 Higashi-Osaka, Japan
  • Molecular mechanisms for the upregulation of Cav3.2 T-type calcium channels in the neuropathic pain.  [通常講演]
    Tomita, S; Sekiguchi, F; Tsubota, M; Kawabata, A
    The 12th International Conference on Protein Phosphatase 2016年10月 口頭発表(一般) Higashi-Osaka, Japan
  • Targeting HMGB1 and its downstream molecules for treatment of oxaliplatin-induced peripheral neuropathy.  [通常講演]
    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年10月 口頭発表(一般) Higashi-Osaka, Japan
  • 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.  [通常講演]
    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年10月 ポスター発表 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.  [通常講演]
    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年10月 ポスター発表 高槻
  • Involvement of Cav3.2 T-type Ca2+channels in the oxaliplatin-induced neuropathic pain.  [通常講演]
    Tsubota, M
    2016 International Calcium channel Meeting 2016年10月 口頭発表(一般) Hoi An, Vietnam
  • Macrophage-derived HMGB1 participates in lipopolysaccharide-induced inflammatory hyperalgesia and paclitaxel-induced neuropathic pain in mice.  [通常講演]
    Domoto, R; Yamasoba, D; Yamanishi, H; Sekiguchi, F; Tsubota, M; Nishibori, M; Kawabata, A
    16th World Congress on Pain 2016年09月 ポスター発表 Yokohama, Japan
  • Cav3.2 T-type calcium channels contribute to oxaliplatin-induced neuropathic pain in mice.  [通常講演]
    Miyazaki, T; Fukuda, R; Tsubota, M; Kawabata, A
    16th World Congress on Pain 2016年09月 ポスター発表 Yokohama, Japan
  • Tacrolimus causes relapse of pancreatic pain through TRPV1 activation during the recovery from cerulein-induced pancreatitis in mice.  [通常講演]
    Terada, Y; Tsubota, M; Sekiguchi, F; Wada, K; Kuwahara, T; Takada, M; Kawabata, A
    16th World Congress on Pain 2016年09月 ポスター発表 Yokohama, Japan
  • 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.  [通常講演]
    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年08月 ポスター発表 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.  [通常講演]
    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年08月 ポスター発表 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.  [通常講演]
    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年08月 口頭発表(一般) 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.  [通常講演]
    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年08月 口頭発表(一般) 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.  [通常講演]
    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年08月 口頭発表(一般) 仙台
  • High mobility group box 1 mediates substance P-induced bladder pain in mice, a model for bladder pain syndrome.  [通常講演]
    Maeda, M; Irie, Y; Tsubota, M; Kubo, L; Sekiguchi, F; Ishikura, H; Nishibori, M; Kawabata, A
    Physiology 2016 2016年07月 ポスター発表 Dublin, Ireland
  • Macrophage-derived high mobility group box 1 mediates H2S-dependent bladder pain in mice with cyclophosphamide-induced cystitis.  [通常講演]
    Hiramoto, S; Tsubota, M; Yamguchi, K; Tanaka, J; Sekiguchi, F; Ishikura, H; Nishibori, M; Kawabata, A
    Physiology 2015 2016年07月 ポスター発表 Dublin, Ireland
  • Involvement of macrophage-derived high mobility group box 1 in paclitaxel-induced neuropathic pain in mice.  [通常講演]
    Domoto, R; Yamasoba, D; Yamanishi, H; Sekiguchi, F; Tsubota, M; Nishibori, M; Kawabata, A
    Physiology 2014 2016年07月 ポスター発表 Dublin, Ireland
  • High mobility group box 1 mediates pancreatic pain in mice.  [通常講演]
    Kawabata, A; Irie, Y; Tsubota, M; Sekiguchi, F; Ishikura, H; Nishibori, M
    Physiology 2012 2016年07月 ポスター発表 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.  [通常講演]
    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年06月 口頭発表(一般) 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.  [通常講演]
    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年06月 口頭発表(一般) 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.  [通常講演]
    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年06月 口頭発表(一般) 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.  [通常講演]
    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年06月 口頭発表(一般) 札幌
  • 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)  [通常講演]
    尾崎友香; 坪田真帆; 川畑篤史
    日本薬学会第136年会 2016年03月 シンポジウム・ワークショップパネル(公募) 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.  [通常講演]
    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年03月 ポスター発表 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.  [通常講演]
    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年03月 ポスター発表 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.  [通常講演]
    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年03月 口頭発表(一般) 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.  [通常講演]
    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年03月 口頭発表(一般) 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.  [通常講演]
    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年03月 口頭発表(一般) 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.  [通常講演]
    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年03月 口頭発表(一般) 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.  [通常講演]
    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年12月 口頭発表(一般) 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.  [通常講演]
    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年12月 口頭発表(一般) 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.  [通常講演]
    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年11月 口頭発表(一般) 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.  [通常講演]
    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年11月 口頭発表(一般) 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.  [通常講演]
    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年11月 口頭発表(一般) 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.  [通常講演]
    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年11月 口頭発表(一般) 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.  [通常講演]
    Tomita, S; Sekiguchi, F; Tsubota, M; Kawabata, A
    Neuroscience 2015 2015年10月 ポスター発表 Chicago, USA
  • The electrophysiological property and antihyperalgesic activity of sophoraflavanone G and 6prenylnaringenin, novel T-type calcium channel blockers.  [通常講演]
    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年10月 ポスター発表 Chicago, USA
  • Zinc deficiency aggravates bladder pain accompanying cyclophosphamide-induced cystitis through the enhanced activity of Cav3.2 T-type Ca2+ channels in mice.  [通常講演]
    Ozaki, T; Matsuoka, J; Tsubota, M; Tomita, S; Sekiguchi, F; Minami, T; Kawabata, A
    Neuroscience 2015 2015年10月 ポスター発表 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.  [通常講演]
    Irie, Y; Tsubota, M; Sekiguchi, F; Ishikura, H; Nishibori, M; Kawabata, A
    Neuroscience 2015 2015年10月 ポスター発表 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.  [通常講演]
    Kawabata, A; Tsubota, M; Yamaguchi, K; Hiramoto, S; Sekiguchi, F; Tanaka, J; Ishikura, H; Nishibori, M
    Neuroscience 2015 2015年10月 ポスター発表 Chicago, USA
  • Vitamin C deficiency aggravates hydrogen sulfide-induced pain/hyperalgesia and chemotherapy-induced neuropathy in mice: possible involvement of T-type calcium channels.  [通常講演]
    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年09月 ポスター発表 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  [通常講演]
    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年08月 ポスター発表 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  [通常講演]
    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年08月 ポスター発表 船橋
  • 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  [通常講演]
    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年06月 口頭発表(一般) 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  [通常講演]
    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年06月 口頭発表(一般) 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  [通常講演]
    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年03月 ポスター発表 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  [通常講演]
    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年03月 ポスター発表 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  [通常講演]
    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年03月 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  [通常講演]
    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年03月 口頭発表(一般) 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  [通常講演]
    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年03月 口頭発表(一般) 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  [通常講演]
    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年03月 口頭発表(一般) 名古屋
  • HMGB1を標的とする内臓痛治療  [通常講演]
    坪田真帆; 川畑篤史
    第88回日本薬理学会年会 2015年03月 シンポジウム・ワークショップパネル(公募) 名古屋
  • Involvement of high mobility group box 1 in substance P-induced cystitis-related bladder pain in mice  [通常講演]
    Irie, Y; Kubo, L; Tsubota, M; Sekiguchi, F; Ishimura, H; Nishibori, M; Kawabata, A
    Pharmacology 2014 2014年12月 ポスター発表 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  [通常講演]
    Ozaki, T; Tsubota, M; Kawabata, A
    Pharmacology 2014 2014年12月 ポスター発表 London, UK
  • Effect of tacrolimus on caerulein-induced pancreatitis-related pain in mice  [通常講演]
    Terada, Y; Tsubota, M; Sekiguchi, F; Wada, K; Kuwahara, T; Takada, M; Kawabata, K
    Pharmacology 2014 2014年12月 ポスター発表 London, UK
  • High mobility group box 1 as a target for prevention and therapeutic treatment of chemotherapy-induced neuropathic pain.  [通常講演]
    Kawabata, A; Kawaishi, Y; Nishida, T; Yamanishi, H; Kamitani, N; Tsubota, M; Sekiguchi, F; Ishikura, H; Nishibori, M
    Pharmacology 2014 2014年12月 口頭発表(一般) 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  [通常講演]
    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年10月 口頭発表(一般) 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  [通常講演]
    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年10月 口頭発表(一般) 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  [通常講演]
    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年10月 口頭発表(一般) 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.  [通常講演]
    Ozaki, T; Tsubota, M; Kawabata, A
    International Symposium “Gasotransmitters: Physiology and Pathophysiology” 2014年09月 ポスター発表 Kazan, Russia
  • Capsaicin誘起結腸痛に対するcalcineurin阻害薬FK506の増強効果  [通常講演]
    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年08月 ポスター発表 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  [通常講演]
    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年08月 ポスター発表 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  [通常講演]
    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年08月 ポスター発表 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  [通常講演]
    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
    生体機能と創薬シンポジウム2014 2014年08月 ポスター発表 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  [通常講演]
    坪田真帆; 川畑篤史
    生体機能と創薬シンポジウム2014 2014年08月 シンポジウム・ワークショップパネル(公募) 東大阪
  • Prevention and reversal of chemotherapy-induced neuropathic pain by HMGB1 neutralization in rodents  [通常講演]
    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年07月 ポスター発表 Milan, Italy
  • 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  [通常講演]
    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年06月 口頭発表(一般) 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  [通常講演]
    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年06月 口頭発表(一般) 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  [通常講演]
    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年06月 口頭発表(一般) 岡山
  • Ascorbic acid deficiency augments hyperalgesia induced by hydrogen sulfide in mice  [通常講演]
    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年06月 ポスター発表 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  [通常講演]
    坪田真帆; 川畑篤史
    日本薬学会第134年会 2014年03月 シンポジウム・ワークショップパネル(公募) 熊本
  • 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  [通常講演]
    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年03月 ポスター発表 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  [通常講演]
    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年03月 ポスター発表 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  [通常講演]
    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年03月 口頭発表(一般) 仙台
  • Involvement of high mobility group box 1 in cyclophosphamide-induced cystitis-related bladder pain in mice.  [通常講演]
    Kawabata, A; Tanaka, J; Yamaguchi, K; Ishikura, H; Tsubota, M
    Pharmacology 2013 2013年12月 ポスター発表 London, UK
  • Recombinant human soluble thrombomodulin abolishes bladder pain accompanying cyclophosphamide-induced cystitis in mice  [通常講演]
    Tanaka, J; Ishikura, H; Yamaguchi, K; Tsubota, M; Sekiguchi, F; Seki, Y; Kawabata, A
    Neuroscience 2013 2013年11月 ポスター発表 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  [通常講演]
    Terada, Y; Fujimura, M; Nishimukra, S; Tsubota, M; Kawabata, A
    Neuroscience 2013 2013年11月 ポスター発表 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.  [通常講演]
    Sekiguchi, F; Kawara, Y; Kanaoka, D; Kawaishi, Y; Tsubota, M; Kawakami, E; Ozaki, T; Yoshida, S; Okubo, T; Kawabata, A
    Neuroscience 2013 2013年11月 ポスター発表 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  [通常講演]
    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年11月 ポスター発表 京都
  • 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  [通常講演]
    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年08月 ポスター発表 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  [通常講演]
    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年08月 ポスター発表 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  [通常講演]
    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年08月 ポスター発表 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  [通常講演]
    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年08月 ポスター発表 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  [通常講演]
    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年08月 ポスター発表 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  [通常講演]
    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年08月 ポスター発表 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  [通常講演]
    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年07月 口頭発表(一般) 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  [通常講演]
    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年07月 口頭発表(一般) 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  [通常講演]
    関口富美子; 坪田真帆; 川畑篤史
    第35回日本疼痛学会 2013年07月 口頭発表(一般) 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  [通常講演]
    川畑篤史; 坪田真帆; 関口富美子
    第35回日本疼痛学会 2013年07月 口頭発表(一般) 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  [通常講演]
    坪田真帆; 川畑篤史
    第90回日本生理学会大会 2013年03月 シンポジウム・ワークショップパネル(公募) 東京
  • 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  [通常講演]
    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年11月 口頭発表(一般) 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  [通常講演]
    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年11月 口頭発表(一般) 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  [通常講演]
    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年11月 口頭発表(一般) 豊中
  • Recombinant soluble human thrombomodulin abolishes inflammatory hyperalgesia in rats  [通常講演]
    Tanaka, J; Seki, Y; Yamaguchi, K; Ishikura, H; Tsubota, M; Sekiguchi, F; Kawabata, A
    Neuroscience 2012 2012年10月 ポスター発表 New Orleans, USA
  • Blocking T-type calcium channels protects against the brain injury induced by middle cerebral artery occlusion and reperfusion in mice  [通常講演]
    Kawabata, A; Nishikawa, H; Matsuda, S; Fukatsu, A; Kurokawa, Y; Tsubota-Matsunami, M; Tokuyama, S
    Neuroscience 2012 2012年10月 ポスター発表 New Orleans, 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  [通常講演]
    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 ポスター発表 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  [通常講演]
    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 ポスター発表 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  [通常講演]
    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 ポスター発表 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  [通常講演]
    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 ポスター発表 福岡

MISC

受賞

  • 2021年08月 生体機能と創薬シンポジウム2021 優秀発表賞
     内臓痛の発症におけるCav3.2 T型Ca2+チャネルおよびHMGB1の役割 
    受賞者: 坪田真帆
  • 2020年10月 日本薬学会関西支部総会・大会 日本薬学会関西支部奨励賞
     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 
    受賞者: 坪田真帆
  • 2008年03月 第26回Cytoprotection研究会 奨励賞
     結腸内腔硫化水素により誘起される内臓痛の発現メカニズムの解析 
    受賞者: 松波(坪田)真帆
  • 2007年08月 The 4th Pfizer Science and Research Symposium Excellence Award
     Luminal hydrogen sulfide in mouse colon: a novel mediator for visceral pain 
    受賞者: 松波(坪田)真帆

共同研究・競争的資金等の研究課題

  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2023年04月 -2026年03月 
    代表者 : 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)
    研究期間 : 2021年04月 -2024年03月 
    代表者 : 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)
    研究期間 : 2020年04月 -2023年03月 
    代表者 : 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ことを明らかにし、H2S合成酵素阻害薬が新たながん治療薬として、さらに、がん化学療法の副作用であるCIPNの軽減の両面において高い有用性を示す可能性を明らかにすることを目的としている。2020年度は、ヒト多発性骨髄腫(multiple myeloma, MM)由来KMS-11細胞と、MM治療薬ボルテゾミブ(BTZ)の耐性株KMS-11/BTZ細胞いずれの細胞増殖も、H2S合成酵素の1つであるcystathionine-β-synthase(CBS)の阻害薬により顕著に抑制され、この抑制効果はH2S供与体のNa2SあるいはGYY4137により一部回復することから、KMS-11およびKMS-11/BTZ細胞の増殖は主にCBSにより産生された内因性H2Sにより促進的に調節されていることを示した。そこで2021年度は、これまで使用されていたCBS阻害薬の選択性が高くないことを考慮し、新たなCBS阻害薬の創製に向けた実験を試みた。近年、パーキンソン病治療薬である芳香族L-アミノ酸脱炭酸酵素阻害薬(AADC-I)のベンセラジドがCBS阻害活性を有することが示されたことから、ベンセラジドと別のAADC-Iであるカルビドパについて、CBS阻害活性を測定したところ、どちらも強いCBS阻害活性を示し、その効果はカルビドパでより強力であった。さらに、ベンセラジドとカルビドパは、KMS-11細胞およびKMS-11/BTZ細胞の細胞増殖を強力に抑制し、また、これら細胞増殖に関わるNF-κB活性化も有意に阻害したことから、これらAADC-Iが新たなCBS阻害薬の創製のリード化合物となる可能性が示唆された。
  • エストロゲン分泌低下による抗がん剤パクリタキセル誘起末梢神経障害の増悪機構の解析:マクロファージ由来HMGB1の関与
    公益財団法人山口記念科学振興財団:公益財団法人山口記念科学振興財団 助成金
    研究期間 : 2021年01月 -2021年12月
  • 日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2018年04月 -2021年03月 
    代表者 : 坪田 真帆
     
    本年度はブチル酸誘起過敏性腸症候群の発症にカンナビノイドCB2受容体を多く発現するマクロファージが関与するかについて検討を行い、さらに我々のグループが新たに同定したT型カルシウムチャネル阻害薬6-prenylnaringenin (6-PNG) およびCB1受容体刺激薬ACEAが本モデルにおける結腸過敏および関連痛覚過敏を抑制するかについて明らかにした。蛍光免疫染色法により、ブチル酸投与マウスの結腸および脊髄後根神経節 (DRG) におけるマクロファージ集積を確認したところ、投与開始3日後のマウスの結腸組織およびDRGにおいてコントロール群と比較してマクロファージ数の増加が認められたが、投与開始6日後では変化が見られなかった。さらに、ブチル酸誘起結腸過敏および関連痛覚過敏の発症は、マクロファージ/ミクログリア阻害薬ミノサイクリン、マクロファージ枯渇薬リポソーム化クロドロネートにより阻止された。一方、結腸痛成立後にミノサイクリンを投与しても無効であった。また、6-PNGの腹腔内投与は、ブチル酸誘起結腸過敏および関連痛覚過敏を著明に抑制した。一方、ACEAは、ブチル酸誘起結腸過敏には抑制効果を示したが、関連痛覚過敏には無効であった。以上のことからブチル酸誘起過敏性腸症候群の発症にマクロファージが関与する可能性が示唆された。さらに、ブチル酸誘起結腸過敏および関連痛覚過敏にT型カルシウムチャネル阻害薬が有効であることが明らかになった。
  • 日本学術振興会:科学研究費助成事業 若手研究(B)
    研究期間 : 2015年04月 -2018年03月 
    代表者 : 坪田 真帆
     
    本研究により、マウスのbutyrate誘起IBSモデルでは、Cav3.2 T-channelの機能亢進が起こっており、これによってTRPV1の直接刺激あるいはPAR2刺激を介する間接的活性化、さらにTRPA1刺激に対する結腸痛覚過敏が生じている可能性が示唆された。本知見は、IBSの発症にかかわる分子メカニズムを解明するための重要な示唆を与えるものと考えられる。
  • 日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2014年04月 -2017年03月 
    代表者 : 川畑 篤史; 関口 富美子; 坪田 真帆
     
    核内蛋白HMGB1はdamage-associated molecular patternsとして、病態時に細胞外に放出される。今回は、癌化学療法誘起神経障害性疼痛および内臓痛におけるHMGB1の役割を解析した。その結果、HMGB1は、RAGE、Toll-like receptor 4、CXCR4などの細胞膜受容体を介して癌化学療法誘起神経障害性疼痛や膵炎に伴う膵臓痛の発症および維持に関与することが明らかとなった。
  • 日本学術振興会:科学研究費助成事業 若手研究(B)
    研究期間 : 2011年04月 -2015年03月 
    代表者 : 坪田 真帆
     
    膀胱組織においてサブスタンスPはおそらくNK1受容体を介して硫化水素合成酵素シスタチオニン-γ-リアーゼ (CSE)のup-regulationを引き起こし、これによって膀胱組織内で生成された硫化水素が炎症の進行を促進するとともにCav3.2 T型カルシウムチャネルを活性化することで膀胱痛の発現および維持に関与することが明らかとなった。今後、これらのシグナル経路を標的とした薬物が間質性膀胱炎の新たな治療薬として開発されることが期待される。
  • 日本学術振興会:科学研究費助成事業 基盤研究(C)
    研究期間 : 2011年 -2013年 
    代表者 : 川畑 篤史; 関口 富美子; 坪田 真帆
     
    T型カルシムチャネルの3つのサブタイプのうち、Cav3.2は侵害受容ニューロンの末梢終末に豊富に発現し、痛みの情報伝達に重要な役割を果たしている。今回は、Cav3.2のリン酸化および脱リン酸化による機能調節とそれによる疼痛制御の分子メカニズムを解析した。その結果、プロスタグランジンEP4受容体刺激により活性化されるPKAが、足場タンパクAKAP150依存的にCav3.2をリン酸化し、チャネル機能を増強することで痛覚過敏を誘起すること、また、脱リン酸化酵素であるカルシニューリンはCav3.2の機能を抑制していることが明らかとなった。

委員歴

  • 2021年 - 現在   日本薬理学会 次世代の会   運営委員
  • 2015年 - 現在   日本薬理学会   学術評議員
  • 2013年 - 現在   日本薬学会薬理系薬学部会   若手世話人

その他のリンク

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