KINDAI UNIVERSITY


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HARA Yuta

Profile

FacultyDepartment of Pharmacy
PositionAssistant Professor
DegreePh.D.Pharmaceutical Sciences
Commentator Guidehttps://www.kindai.ac.jp/meikan/2097-hara-yuta.html
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Last Updated :2020/08/10

Education and Career

Education

  •   2007 04  - 2011 03 , Osaka University, School of Pharmaceutical Sciences

Academic & Professional Experience

  •   2017 04 ,  - 現在, Faculty of Pharmacy, Kindai University

Research Activities

Research Interests

  • Pharmacology

Published Papers

  • Anti-tumor effects of an antagonistic mAb against the ASCT2 amino acid transporter on KRAS-mutated human colorectal cancer cells., Hara Y, Minami Y, Yoshimoto S, Hayashi N, Yamasaki A, Ueda S, Masuko K, Masuko T, Cancer medicine, Cancer medicine, Nov. 2019 , Refereed
  • [Chronic Activation of the Dopaminergic Neuronal Pathway Improves Behavioral Abnormalities in the Prenatal Valproic Acid Exposure Mouse Model of Autism Spectrum Disorder]., Hara Y, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 139(11), 1391 - 1396, 2019 , Refereed
  • mS-11, a mimetic of the mSin3-binding helix in NRSF, ameliorates social interaction deficits in a prenatal valproic acid-induced autism mouse model., Kawase H, Ago Y, Naito M, Higuchi M, Hara Y, Hasebe S, Tsukada S, Kasai A, Nakazawa T, Mishina T, Kouji H, Takuma K, Hashimoto H, Pharmacology, biochemistry, and behavior, Pharmacology, biochemistry, and behavior, 176, 1 - 5, Nov. 2018 , Refereed
  • Anti-tumor effects of mAb against L-type amino acid transporter 1 (LAT1) bound to human and monkey LAT1 with dual avidity modes., Shiho Ueda, Hidemi Hayashi, Takako Miyamoto, Shinya Abe, Kana Hirai, Kanji Matsukura, Hideki Yagi, Yuta Hara, Kinji Yoshida, Shogo Okazaki, Masakazu Tamura, Yuki Abe, Toshinori Agatsuma, Shin-Ichiro Niwa, Kazue Masuko, Takashi Masuko, Cancer science, Cancer science, 110(2), 674 - 685, Feb. 2019 , Refereed
    Summary:L-Type amino acid transporter 1 (LAT1) disulfide linked to CD98 heavy chain (hc) is highly expressed in most cancer cells, but weakly expressed in normal cells. In the present study, we developed novel anti-LAT1 mAbs and showed internalization activity, inhibitory effects of amino acid uptake and cell growth and antibody-dependent cellular cytotoxicity, as well as in vivo antitumor effects in athymic mice. Furthermore, we examined the reactivity of mAbs with LAT1 of Macaca fascicularis to evaluate possible side-effects of antihuman LAT1 mAbs in clinical trials. Antihuman LAT1 mAbs reacted with ACHN human and MK.P3 macaca kidney-derived cells, and this reactivity was significantly decreased by siRNAs against LAT1. Macaca LAT1 cDNA was cloned from MK.P3, and only two amino acid differences between human and macaca LAT1 were seen. RH7777 rat hepatoma and HEK293 human embryonic kidney cells expressing macaca LAT1 were established as stable transfectants, and antihuman LAT1 mAbs were equivalently reactive against transfectants expressing human or macaca LAT1. Dual (high and low) avidity modes were detected in transfectants expressing macaca LAT1, MK.P3, ACHN and HCT116 human colon cancer cells, and KA values were increased by anti-CD98hc mAb, suggesting anti-LAT1 mAbs detect an epitope on LAT1-CD98hc complexes on the cell surface. Based on these results, LAT1 may be a promising anticancer target and Macaca fascicularis can be used in preclinical studies with antihuman LAT1 mAbs.
  • A CCR4 antagonist ameliorates atopic dermatitis-like skin lesions induced by dibutyl phthalate and a hydrogel patch containing ovalbumin., Kazuhiko Matsuo, Shota Hatanaka, Yuta Kimura, Yuta Hara, Keiji Nishiwaki, Ying-Shu Quan, Fumio Kamiyama, Naoki Oiso, Akira Kawada, Kenji Kabashima, Takashi Nakayama, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 109, 1437 - 1444, Jan. 2019 , Refereed
    Summary:CCR4 is a chemokine receptor highly expressed by Th2 cells, and regarded as a potential therapeutic target for atopic dermatitis (AD). CCL17 and CCL22 are the CCR4 ligands, and thymic stromal lymphopoietin (TSLP) is shown to promote the expression of CCL17 and CCL22 by dendritic cells. Here, by using dibutyl phthalate (DBP), a TSLP inducer, and a hydrogel patch as a transcutaneous delivery device for ovalbumin, we developed a novel murine AD model and investigated the effect of Compound 22, a CCR4 antagonist. We first found that the mRNA expression of TSLP together with CCL17 and CCL22 was increased in the skins treated with DBP. Furthermore, the topical application of ovalbumin and DBP efficiently and rapidly induced AD-like skin lesions in BALB/c mice, which were characterized by ear swelling accompanied by infiltration of eosinophils, mast cells, and CCR4-expressing Th2 cells in the skin lesions, and elevated total IgE levels in the sera. Using this AD model, we demonstrated that cutaneous administration of Compound 22 inhibited Th2 cell infiltration and ameliorated the AD-like skin lesions. These results suggest that our AD model could be useful for studying new therapeutic strategies. Collectively, CCR4 antagonists may be a promising approach for treating AD.
  • Ascorbic acid derivative DDH-1 ameliorates psoriasis-like skin lesions in mice by suppressing inflammatory cytokine expression., Kosuke Kitahata, Kazuhiko Matsuo, Yuta Hara, Takanori Naganuma, Naoki Oiso, Akira Kawada, Takashi Nakayama, Journal of pharmacological sciences, Journal of pharmacological sciences, 138(4), 284 - 288, Dec. 2018 , Refereed
    Summary:Psoriasis is a chronic inflammatory skin disease in which inflammatory cytokines play a major role in its pathogenesis. Because DDH-1, a novel amphipathic ascorbic acid derivative, has been recently shown to reduce inflammatory cytokine expression in human keratinocytes in vitro, we investigated its effect on imiquimod-induced psoriasis-like skin lesions in C57BL/6 mice. We first found that IL-1β and TNF-α mRNA expression was significantly decreased in the skin lesions treated with DDH-1. Furthermore, cutaneous administration of DDH-1 ameliorated psoriasis-like skin lesions. These results suggest that DDH-1 may be effective in the prevention and supplemental treatment of psoriasis.
  • Inhibition of tumor formation and metastasis by a monoclonal antibody against lymphatic vessel endothelial hyaluronan receptor 1., Yuta Hara, Ryota Torii, Shiho Ueda, Erina Kurimoto, Eri Ueda, Hiroshi Okura, Yutaka Tatano, Hideki Yagi, Yoshiya Ohno, Toshiyuki Tanaka, Kazue Masuko, Takashi Masuko, Cancer science, Cancer science, 109(10), 3171 - 3182, Oct. 2018 , Refereed
    Summary:Although cancer metastasis is associated with poor prognosis, the mechanisms of this event, especially via lymphatic vessels, remain unclear. Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) is expressed on lymphatic vessel endothelium and is considered to be a specific marker of lymphatic vessels, but it is unknown how LYVE-1 is involved in the growth and metastasis of cancer cells. We produced rat monoclonal antibodies (mAb) recognizing the extracellular domain of mouse LYVE-1, and investigated the roles of LYVE-1 in tumor formation and metastasis. The mAb 38M and 64R were selected from hybridoma clones created by cell fusion between spleen cells of rats immunized with RH7777 rat hepatoma cells expressing green fluorescent protein (GFP)-fused mouse LYVE-1 proteins and mouse myeloma cells. Two mAb reacted with RH7777 and HEK293F human embryonic kidney cells expressing GFP-fused mouse LYVE-1 proteins in a GFP expression-dependent manner, and each recognized a distinct epitope. On immunohistology, the 38M mAb specifically stained lymphatic vessels in several mouse tissues. In the wound healing assay, the 64R mAb inhibited cell migration of HEK293F cells expressing LYVE-1 and mouse lymphatic endothelial cells (LEC), as well as tube formation by LEC. Furthermore, this mAb inhibited primary tumor formation and metastasis to lymph nodes in metastatic MDA-MB-231 xenograft models. This shows that LYVE-1 is involved in primary tumor formation and metastasis, and it may be a promising molecular target for cancer therapy.
  • A Highly Active Form of XCL1/Lymphotactin Functions as an Effective Adjuvant to Recruit Cross-Presenting Dendritic Cells for Induction of Effector and Memory CD8+ T Cells., Kazuhiko Matsuo, Kosuke Kitahata, Fumika Kawabata, Momo Kamei, Yuta Hara, Shiki Takamura, Naoki Oiso, Akira Kawada, Osamu Yoshie, Takashi Nakayama, Frontiers in immunology, Frontiers in immunology, 9, 2775 - 2775, 2018 , Refereed
    Summary:The chemokine receptor XCR1 is known to be selectively expressed by cross-presenting dendritic cells (DCs), while its ligand XCL1/lymphotactin is mainly produced by activated CD8+ T cells and natural killer cells. Recent studies have shown that XCL1-antigen fusion proteins efficiently induce CD8+ T cell responses by preferentially delivering antigens to XCR1+ DCs. However, XCL1 per se was found to be a poor adjuvant for induction of CD8+ T cell responses. XCL1 is unique because of its lack of one of the two disulfide bonds commonly conserved in all other chemokines and thus has an unstable structure with a relatively weak chemokine activity. In the present study, we generated a variant form of murine XCL1 termed mXCL1-V21C/A59C that contained a second disulfide bond to stabilize its chemokine structure. We confirmed that mXCL1-V21C/A59C had much more potent chemotactic and calcium mobilization activities than the wild type XCL1 (mXCL1-WT). Intradermal injection of mXCL1-V21C/A59C, but not that of mXCL1-WT, significantly increased the accumulation of XCR1+CD103+ DCs in the injection site, and most of the accumulated XCR1+CD103+ DCs were found to take up co-injected ovalbumin (OVA). Furthermore, recruited XCR1+CD103+ DCs efficiently migrated to the draining lymph nodes and stayed for a prolonged period of time. Consequently, mXCL1-V21C/A59C strongly induced OVA-specific CD8+ T cells. The combination of OVA and mXCL1-V21C/A59C well protected mice from E.G7-OVA tumor growth in both prophylactic and therapeutic protocols. Finally, memory CTL responses were efficiently induced in mice immunized with OVA and mXCL1-V21C/A59C. Although intradermal injection of OVA and polyinosinic-polycytidylic acid (poly(I:C)) as an adjuvant also induced CD8+ T cell responses to OVA, poly (I:C) poorly recruited XCR1+CD103+ DCs in the injection site and failed to induce significant memory CTL responses to OVA. Collectively, our findings demonstrate that a highly active form of XCL1 is a promising vaccine adjuvant for cross-presenting DCs to induce antigen-specific effector and memory CD8+ T cells.
  • Risperidone and aripiprazole alleviate prenatal valproic acid-induced abnormalities in behaviors and dendritic spine density in mice, Yuta Hara, Yukio Ago, Atsuki Taruta, Shigeru Hasebe, Haruki Kawase, Wataru Tanabe, Shinji Tsukada, Takanobu Nakazawa, Hitoshi Hashimoto, Toshio Matsuda, Kazuhiro Takuma, PSYCHOPHARMACOLOGY, PSYCHOPHARMACOLOGY, 234(21), 3217 - 3228, Nov. 2017 , Refereed
    Summary:Rodents exposed prenatally to valproic acid (VPA) exhibit autism spectrum disorder (ASD)-like behavioral abnormalities. We recently found that prenatal VPA exposure causes hypofunction of the prefrontal dopaminergic system in mice. This suggests that the dopaminergic system may be a potential pharmacological target for treatment of behavioral abnormalities in ASD patients. In the present study, we examined the effects of antipsychotic drugs, which affect the dopaminergic system, on the social interaction deficits, recognition memory impairment, and reduction in dendritic spine density in the VPA mouse model of ASD. Both acute and chronic administrations of the atypical antipsychotic drugs risperidone and aripiprazole increased prefrontal dopamine (DA) release, while the typical antipsychotic drug haloperidol did not. Chronic risperidone and aripiprazole, but not haloperidol, increased the expression of c-Fos in the prefrontal cortex, although they all increased c-Fos expression in the striatum. Chronic, but not acute, administrations of risperidone and aripiprazole improved the VPA-induced social interaction deficits and recognition memory impairment, as well as the reduction in dendritic spine density in the prefrontal cortex and hippocampus. In contrast, chronic administration of haloperidol did not ameliorate VPA-induced abnormalities in behaviors and dendritic spine density. These findings indicate that chronic risperidone and aripiprazole treatments improve VPA-induced abnormalities in behaviors and prefrontal dendritic spine density, which may be mediated by repeated elevation of extracellular DA in the prefrontal cortex. Our results also imply that loss of prefrontal dendritic spines may be involved in the abnormal behaviors in the VPA mouse model of ASD.
  • Oxytocin attenuates deficits in social interaction but not recognition memory in a prenatal valproic acid-induced mouse model of autism, Yuta Hara, Yukio Ago, Momoko Higuchi, Shigeru Hasebe, Takanobu Nakazawa, Hitoshi Hashimoto, Toshio Matsuda, Kazuhiro Takuma, HORMONES AND BEHAVIOR, HORMONES AND BEHAVIOR, 96, 130 - 136, Nov. 2017 , Refereed
    Summary:Recent studies have reported that oxytocin ameliorates behavioral abnormalities in both animal models and individuals with autism spectrum disorders (ASD). However, the mechanisms underlying the ameliorating effects of oxytocin remain unclear. In this study, we examined the effects of intranasal oxytocin on impairments in social interaction and recognition memory in an ASD mouse model in which animals are prenatally exposed to valproic acid (VPA). We found that a single intranasal administration of oxytocin restored social interaction deficits for up to 2 h in mice prenatally exposed to VPA, but there was no effect on recognition memory impairments. Additionally, administration of oxytocin across 2 weeks improved prenatal VPA-induced social interaction deficits for at least 24 h. In contrast, there were no effects on the time spent sniffing in control mice. Immunohistochemical analysis revealed that intranasal administration of oxytocin increased c-Fos expression in the paraventricular nuclei (PVN), prefrontal cortex, and somatosensory cortex, but not the hippocampal CAI and CA3 regions of VPA-exposed mice, suggesting the former regions may underlie the effects of oxytocin. These findings suggest that oxytocin attenuates social interaction deficits through the activation of higher cortical areas and the PVN in an ASD mouse model.
  • Environmental enrichment attenuates behavioral abnormalities in valproic acid-exposed autism model mice, Hiroshi Yamaguchi, Yuta Hara, Yukio Ago, Erika Takano, Shigeru Hasebe, Takanobu Nakazawa, Hitoshi Hashimoto, Toshio Matsuda, Kazuhiro Takuma, BEHAVIOURAL BRAIN RESEARCH, BEHAVIOURAL BRAIN RESEARCH, 333, 67 - 73, Aug. 2017 , Refereed
    Summary:We recently demonstrated that prenatal exposure to valproic acid (VPA) at embryonic day 12.5 causes autism spectrum disorder (ASD)-like phenotypes such as hypolocomotion, anxiety-like behavior, social deficits and cognitive impairment in mice and that it decreases dendritic spine density in the hippocampal CA1 region. Previous studies show that some abnormal behaviors are improved by environmental enrichment in ASD rodent models, but it is not known whether environmental enrichment improves cognitive impairment. In the present study, we examined the effects of early environmental enrichment on behavioral abnormalities and neuromorphological changes in prenatal VPA-treated mice. We also examined the role of dendritic spine formation and synaptic protein expression in the hippocampus. Mice were housed for 4 weeks from 4 weeks of age under either a standard or enriched environment. Enriched housing was found to increase hippocampal brain-derived neurotrophic factor mRNA levels in both control and VPA-exposed mice. Furthermore, in VPA-treated mice, the environmental enrichment improved anxiety-like behavior, social deficits and cognitive impairment, but not hypolocomotion. Prenatal VPA treatment caused loss of dendritic spines in the hippocampal CAl region and decreases in mRNA levels of postsynaptic density protein-95 and SH3 and multiple ankyrin repeat domains 2 in the hippocampus. These hippocampal changes were improved by the enriched housing. These findings suggest that the environmental enrichment improved most ASD-like behaviors including cognitive impairment in the VPA-treated mice by enhancing dendritic spine function.
  • Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain, Yuta Hara, Yukio Ago, Erika Takano, Shigeru Hasebe, Takanobu Nakazawa, Hitoshi Hashimoto, Toshio Matsuda, Kazuhiro Takuma, MOLECULAR AUTISM, MOLECULAR AUTISM, 8, 33, Jun. 2017 , Refereed
    Summary:Background: MicroRNAs, small non-coding RNAs, are highly expressed in the mammalian brain, and the dysregulation of microRNA levels may be involved in neurodevelopmental disorders such as autism spectrum disorder (ASD). In the present study, we examined whether prenatal valproic acid (VPA) exposure affects levels of microRNAs, especially the brain specific and enriched microRNAs, in the mouse embryonic brain. Results: Prenatal exposure to VPA at E12.5 immediately increased miR-132 levels, but not miR-9 or miR-124 levels, in the male embryonic brain. Prenatal exposure to VPA at E12.5 also increased miR-132 levels in the female embryonic brain. We further found that the prenatal exposure to VPA at E12.5 increased mRNA levels of Arc, c-Fos and brain-derived neurotrophic factor in both male and female embryonic brains, prior to miR-132 expression. In contrast, prenatal exposure to VPA at E14.5 did not affect miR-132 levels in either male or female embryonic brain. The prenatal VPA exposure at E12.5 also decreased mRNA levels of methyl-CpG-binding protein 2 and Rho GTPase-activating protein p250GAP, both of which are molecular targets of miR-132. Furthermore, RNA sequence analysis revealed that prenatal VPA exposure caused changes in several microRNA levels other than miR-132 in the embryonic whole brain. Conclusions: These findings suggest that the alterations in neuronal activity-dependent microRNAs levels, including an increased level of miR-132, in the embryonic period, at least in part, underlie the ASD-like behaviors and cortical pathology produced by prenatal VPA exposure.
  • Improvement by Methylphenidate and Atomoxetine of Social Interaction Deficits and Recognition Memory Impairment in a Mouse Model of Valproic Acid-Induced Autism, Yuta Hara, Yukio Ago, Atsuki Taruta, Keisuke Katashiba, Shigeru Hasebe, Erika Takano, Yusuke Onaka, Hitoshi Hashimoto, Toshio Matsuda, Kazuhiro Takuma, AUTISM RESEARCH, AUTISM RESEARCH, 9(9), 926 - 939, Sep. 2016 , Refereed
    Summary:Rodents exposed prenatally to valproic acid (VPA) show autism-related behavioral abnormalities. We recently found that prenatal VPA exposure causes a reduction of dopaminergic activity in the prefrontal cortex of male, but not female, mice. This suggests that reduced prefrontal dopaminergic activity is associated with behavioral abnormalities in VPA-treated mice. In the present study, we examined whether the attention deficit/hyperactivity disorder drugs methylphenidate and atomoxetine (which increase dopamine release in the prefrontal cortex, but not striatum, in mice) could alleviate the behavioral abnormalities and changes in dendritic spine morphology induced by prenatal VPA exposure. We found that methylphenidate and atomoxetine increased prefrontal dopamine and noradrenaline release in VPA-treated mice. Acute treatment with methylphenidate or atomoxetine did not alleviate the social interaction deficits or recognition memory impairment in VPA-treated mice, while chronic treatment for 2 weeks did. Methylphenidate or atomoxetine for 2 weeks also improved the prenatal VPA-induced decrease in dendritic spine density in the prefrontal cortex. The effects of these drugs on behaviors and dendritic spine morphology were antagonized by concomitant treatment with the dopamine-D-1 receptor antagonist SCH39166 or the dopamine-D-2 receptor antagonist raclopride, but not by the alpha(2)-adrenoceptor antagonist idazoxan. These findings suggest that chronic treatment with methylphenidate or atomoxetine improves abnormal behaviors and diminishes the reduction in spine density in VPA-treated mice via a prefrontal dopaminergic system-dependent mechanism. (C) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
  • Reduced prefrontal dopaminergic activity in valproic acid-treated mouse autism model, Yuta Hara, Kazuhiro Takuma, Erika Takano, Keisuke Katashiba, Atsuki Taruta, Kosuke Higashino, Hitoshi Hashimoto, Yukio Ago, Toshio Matsuda, BEHAVIOURAL BRAIN RESEARCH, BEHAVIOURAL BRAIN RESEARCH, 289, 39 - 47, Aug. 2015 , Refereed
    Summary:Previous studies suggest that dysfunction of neurotransmitter systems is associated with the pathology of autism in humans and the disease model rodents, but the precise mechanism is not known. Rodent offspring exposed prenatally to VPA shows autism-related behavioral abnormalities. The present study examined the effect of prenatal VPA exposure on brain monoamine neurotransmitter systems in male and female mice. The prenatal VPA exposure did not affect the levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) and their metabolites in the prefrontal cortex and striatum, while it significantly reduced methamphetamine (METH) (1.0 mg/kg)-induced hyperlocomotion in male offspring. In vivo microdialysis study demonstrated that prenatal VPA exposure attenuated METH-induced increases in extracellular DA levels in the prefrontal cortex, while it did not affect those in extracellular NA and 5-HT levels. Prenatal VPA exposure also decreased METH-induced c-Fos expression in the prefrontal cortex and the mRNA levels of DA D-1 and D-2 receptors in the prefrontal cortex. These effects of VPA were not observed in the striatum. In contrast to male offspring, prenatal VPA exposure did not affect METH-induced increases in locomotor activity and prefrontal DA levels and the D-1 and D-2 receptor mRNA levels in the prefrontal cortex in female offspring. These findings suggest that prenatal VPA exposure causes hypofunction of prefrontal DA system in a sex-dependent way. (C) 2015 Elsevier B.V. All rights reserved.
  • Chronic treatment with valproic acid or sodium butyrate attenuates novel object recognition deficits and hippocampal dendritic spine loss in a mouse model of autism, Kazuhiro Takuma, Yuta Hara, Shunsuke Kataoka, Takuya Kawanai, Yuko Maeda, Ryo Watanabe, Erika Takano, Atsuko Hayata-Takano, Hitoshi Hashimoto, Yukio Ago, Toshio Matsuda, PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 126, 43 - 49, Nov. 2014 , Refereed
    Summary:We recently showed that prenatal exposure to valproic acid (VPA) in mice causes autism-like behavioral abnormalities, including social interaction deficits, anxiety-like behavior and spatial learning disability, in male offspring. In the present study, we examined the effect of prenatal VPA on cognitive function and whether the effect is improved by chronic treatment with WA and sodium butyrate, histone deacetylase inhibitors. In addition, we examined whether the cognitive dysfunction is associated with hippocampal dendritic morphological changes. Mice given prenatal exposure to VPA exhibited novel object recognition deficits at 9 weeks of age, and that the impairment was blocked by chronic (5-week) treatment with WA (30 mg/kg/d, i.p.) or sodium butyrate (1.2 g/kg/d, i.p.) starting at 4 weeks of age. In agreement with the behavioral findings, the mice prenatally exposed to VPA showed a decrease in dendritic spine density in the hippocampal CM region, and the spine loss was attenuated by chronic treatment with sodium butyrate or VPA. Furthermore, acute treatment with sodium butyrate, but not VPA, significantly increased acetylation of histone H3 in the hippocampus at 30 mm, suggesting the difference in the mechanism for the effects of chronic VPA and sodium butyrate. These findings suggest that prenatal VPA-induced cognitive dysfunction is associated with changes in hippocampal dendritic spine morphology. (C) 2014 Elsevier Inc. All rights reserved.
  • Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid, Shunsuke Kataoka, Kazuhiro Takuma, Yuta Hara, Yuko Maeda, Yukio Ago, Toshio Matsuda, INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, 16(1), 91 - 103, Feb. 2013 , Refereed
    Summary:Maternal use of valproic acid (VPA) during pregnancy has been implicated in the aetiology of autism spectrum disorders in children, and rodents prenatally exposed to VPA showed behavioural alterations similar to those observed in humans with autism. However, the exact mechanism for VPA-induced behavioural alterations is not known. To study this point, we examined the effects of prenatal exposure to VPA and valpromide, a VPA analog lacking histone deacetylase inhibition activity, on behaviours, cortical pathology and histone acetylation levels in mice. Mice exposed to VPA at embryonic day 12.5 (E12.5), but not at E9 and E14.5, displayed social interaction deficits, anxiety-like behaviour and memory deficits at age 4-8 wk. In contrast to male mice, the social interaction deficits (a decrease in sniffing behaviour) were not observed in female mice at age 8 wk. The exposure to VPA at E12.5 decreased the number of Nissl-positive cells in the middle and lower layers of the prefrontal cortex and in the lower layers of the somatosensory cortex at age 8 wk. Furthermore, VPA exposure caused a transient increase in acetylated histone levels in the embryonic brain, followed by an increase in apoptotic cell death in the neocortex and a decrease in cell proliferation in the ganglionic eminence. In contrast, prenatal exposure to valpromide at E12.5 did not affect the behavioural, biochemical and histological parameters. Furthermore, these findings suggest that VPA-induced histone hyperacetylation plays a key role in cortical pathology and abnormal autism-like behaviours in mice.
  • Effect of Prenatal Valproic Acid Exposure on Cortical Morphology in Female Mice, Yuta Hara, Yuko Maeda, Shunsuke Kataoka, Yukio Ago, Kazuhiro Takuma, Toshio Matsuda, JOURNAL OF PHARMACOLOGICAL SCIENCES, JOURNAL OF PHARMACOLOGICAL SCIENCES, 118(4), 543 - 546, Apr. 2012 , Refereed
    Summary:We have recently shown that prenatal valproic acid (VPA) exposure causes autism spectrum disorders-like behavioral abnormalities and Nissl-positive cell loss in both prefrontal and somatosensory cortices in male mice. We have also found that VPA-induced social interaction deficits are observed in male but not female offspring. This study demonstrated that the exposure to VPA at embryonic day 12.5 significantly decreased Nissl-positive cell numbers in the prefrontal cortex, but not in the somatosensory cortex, in female offspring. These findings suggest that VPA-induced morphological abnormalities in the somatosensory cortex may be involved in the sex-dependent social interaction deficits.
  • Effect of Prenatal Valproic Acid Exposure on Cortical Morphology in Female Mice, Yuta Hara, Yuko Maeda, Shunsuke Kataoka, Yukio Ago, Kazuhiro Takuma, Toshio Matsuda, JOURNAL OF PHARMACOLOGICAL SCIENCES, JOURNAL OF PHARMACOLOGICAL SCIENCES, 118(4), 543 - 546, Apr. 2012 , Refereed
    Summary:We have recently shown that prenatal valproic acid (VPA) exposure causes autism spectrum disorders-like behavioral abnormalities and Nissl-positive cell loss in both prefrontal and somatosensory cortices in male mice. We have also found that VPA-induced social interaction deficits are observed in male but not female offspring. This study demonstrated that the exposure to VPA at embryonic day 12.5 significantly decreased Nissl-positive cell numbers in the prefrontal cortex, but not in the somatosensory cortex, in female offspring. These findings suggest that VPA-induced morphological abnormalities in the somatosensory cortex may be involved in the sex-dependent social interaction deficits.

Misc

  • ASCT2アミノ酸トランスポーターに対するモノクローナル抗体作製とその抗腫瘍活性の評価, 原雄大, 南侑志, 吉本蒼司, 益子高, 日本薬学会年会要旨集(CD-ROM), 138th, ROMBUNNO.26PA‐pm193,   2018 , http://jglobal.jst.go.jp/public/201802215318404329
  • 前頭葉を標的とする自閉症スペクトラム障害の新たな治療戦略の可能性, 田熊一敞, 田熊一敞, 田熊一敞, 原雄大, 原雄大, 吾郷由希夫, 橋本均, 橋本均, 橋本均, 橋本均, 中澤敬信, 中澤敬信, 松田敏夫, 日本臨床精神神経薬理学会プログラム・抄録集, 28th, 130,   2018 , http://jglobal.jst.go.jp/public/201802228011620466
  • Regulation of neuropsychiatric and neurodevelopmental disorders by juvenile environmental factors, 田熊一敞, 田熊一敞, 吾郷由希夫, 原雄大, 長谷部茂, 中澤敬信, 中澤敬信, 橋本均, 橋本均, 橋本均, 松田敏夫, 日本生物学的精神医学会誌, 28, 1, 22‐26,   2017 03 25 , 10.11249/jsbpjjpp.28.1_22, http://jglobal.jst.go.jp/public/201702265980255383
  • 自閉スペクトラム症モデルマウスの社会性行動障害に有効な抗てんかん作用を有する医薬品の探索, 三浦大樹, 笠井淳司, 彌永祐輔, 原雄大, 中澤敬信, 中澤敬信, 吾郷由希夫, 田熊一敞, 田熊一敞, 橋本均, 橋本均, 橋本均, 橋本均, 日本薬理学会近畿部会プログラム・要旨集, 132nd, 31,   2017 , http://jglobal.jst.go.jp/public/201802235446422162
  • 自閉症モデルマウスにおける前頭前皮質ドパミン神経系の異常~ADHD治療薬による行動異常の改善, 吾郷由希夫, 原雄大, 前田優子, 長谷部茂, 橋本均, 橋本均, 松田敏夫, 田熊一敞, 田熊一敞, 日本神経精神薬理学会プログラム・抄録集, 46th, 92,   2016 , http://jglobal.jst.go.jp/public/201602291662335906
  • ドパミン神経賦活薬の慢性投与は胎仔期バルプロ酸曝露マウスの自閉症様行動を改善する, 長谷部茂, 原雄大, 樋口桃子, 吾郷由希夫, 中澤敬信, 中澤敬信, 橋本均, 松田敏夫, 田熊一敞, 田熊一敞, 日本生物学的精神医学会(Web), 38th, 175 (WEB ONLY),   2016 , http://jglobal.jst.go.jp/public/201702222344869175
  • 発育期環境要因による神経精神疾患の発症制御, 田熊一敞, 田熊一敞, 長谷部茂, 原雄大, 中澤敬信, 中澤敬信, 橋本均, 松田敏夫, 吾郷由希夫, 日本生物学的精神医学会(Web), 38th, 14 (WEB ONLY),   2016 , http://jglobal.jst.go.jp/public/201702267096568271
  • 胎仔期バルプロ酸曝露は雄性マウス前頭皮質のドパミン神経機能を低下させる, 原雄大, 高野恵利加, 樽田淳樹, 片芝圭亮, 東野功典, 吾郷由希夫, 松田敏夫, 田熊一敞, 日本薬学会年会要旨集(CD-ROM), 135th, ROMBUNNO.26T-PM19,   2015 , http://jglobal.jst.go.jp/public/201502263216952006
  • 注意欠陥多動性障害治療薬による前頭葉ドパミン神経活性化を介した胎仔期バルプロ酸曝露マウスの行動異常の改善, 原雄大, 吾郷由希夫, 樽田淳樹, 片芝圭亮, 樋口桃子, 長谷部茂, 尾中勇祐, 橋本均, 松田敏夫, 田熊一敞, 田熊一敞, 日本薬理学会近畿部会プログラム・要旨集, 128th, 37,   2015 , http://jglobal.jst.go.jp/public/201502212508481605
  • 胎仔期バルプロ酸曝露の神経細胞の成熟に及ぼす影響, 河内琢也, 田熊一敞, 渡部遼, 井上亜耶, 原雄大, 吾郷由希夫, 松田敏夫, 日本薬理学会近畿部会プログラム・要旨集, 125th, 103,   2014 05 , http://jglobal.jst.go.jp/public/201402218269159135
  • 胎仔期バルプロ酸曝露マウスのメタンフェタミン反応性の低下と前頭葉ドパミン神経系異常, 片芝圭亮, 原雄大, 高野恵利加, 樽田淳樹, 東野功典, 前田優子, 吾郷由希夫, 田熊一敞, 松田敏夫, 次世代を担う創薬・医療薬理シンポジウムプログラム・要旨集, 2014, 64,   2014 , http://jglobal.jst.go.jp/public/201402256750167345
  • 胎仔期バルプロ酸曝露マウスの前頭葉ドパミン神経系異常, 原雄大, 高野恵利加, 片芝圭亮, 樽田淳樹, 東野功典, 前田優子, 吾郷由希夫, 田熊一敞, 松田敏夫, 日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集, 24th-44th, 167,   2014 , http://jglobal.jst.go.jp/public/201402225171064531
  • HDAC阻害作用の精神機能に及ぼす二面性, 片岡駿介, 原雄大, 前田優子, 高野恵利加, 吾郷由希夫, 田熊一敞, 松田敏夫, 次世代を担う若手ファーマ・バイオフォーラム講演要旨集, 11th, 71,   2012 09 , http://jglobal.jst.go.jp/public/201202256332872100
  • 胎仔期バルプロ酸曝露による精神異常行動発現におけるヒストンアセチル化の関与, 前田優子, 片岡駿介, 原雄大, 吾郷由希夫, 田熊一敞, 松田敏夫, 日本薬理学会近畿部会プログラム・要旨集, 119th, 31,   2011 , http://jglobal.jst.go.jp/public/201102269749609663
  • ヒストン脱アセチル化酵素阻害活性を欠いたバルプロ酸アナログ,バルプロミド胎仔期投与の生後の情動行動と大脳皮質細胞数に対する作用, 片岡駿介, 田熊一敞, 原雄大, 前田優子, 吾郷由希夫, 松田敏夫, 日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集, 21st-41st, 159,   2011 , http://jglobal.jst.go.jp/public/201102289597077947