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New therapeutic strategies for irritable bowel syndrome targeting cannabinoid receptors and T-type calcium channels

Research Project

Project/Area Number 18K06710
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47040:Pharmacology-related
Research InstitutionKindai University

Principal Investigator

Tsubota Maho  近畿大学, 薬学部, 講師 (90510123)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords過敏性腸症候群 / T型カルシウム / T型カルシウムチャネル / マクロファージ / カンナビノイド受容体 / HMGB1
Outline of Final Research Achievements

The present study demonstrates that Cav3.2 T-type Ca2+ channels play an important role in butyrate and TNBS-induced colonic pain. On the other hands, CB1 or CB2 receptor agonist did not show a clear effect in these models. We also clarified that, among existing drug, bepridil, an antiarrhythmic drug and antianginal drug, and pimozide, a typical antipsychotic drug, markedly reversed colonic pain. Therefore, our findings support that the development of a more selective drug for T-type Ca2+ channel using bepridil or pimozide as a lead compound could be a new therapeutic strategy for irritable bowel syndrome.

Academic Significance and Societal Importance of the Research Achievements

過敏性腸症候群は、腹痛や便通異常が長期間持続することで患者のQOLは著しく損なわれる。現在、IBSの治療には主に対症療法が用いられているが、発症メカニズムに基づくより有効な治療薬の開発が望まれている。本研究課題では、新たな過敏性腸症候群の痛みの治療戦略として既存医薬品の中でT型カルシウムチャネル阻害活性を有する抗不整脈薬bepridilや定型抗精神病薬pimozideの有効性しめした。今後これらの薬物をリード化合物としてよりT型カルシウムチャネルに選択性の高い薬物を開発することで過敏性腸症候群の新たな治療戦略が構築できると考える。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (28 results)

All 2021 2020 2019 2018

All Journal Article (11 results) (of which Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (17 results) (of which Int'l Joint Research: 7 results)

  • [Journal Article] Effects of Bepridil and Pimozide, Existing Medicines Capable of Blocking T-Type Ca<sup>2+</sup> Channels, on Visceral Pain in Mice2021

    • Author(s)
      Tsubota Maho、Matsui Kazuki、Fukushi Saaya、Okazaki Kyoko、Sekiguchi Fumiko、Kawabata Atsufumi
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 44 Issue: 3 Pages: 461-464

    • DOI

      10.1248/bpb.b20-00742

    • NAID

      130007993457

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2021-03-01
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Essential role of Cav3.2 T-type calcium channels in butyrate-induced colonic pain and nociceptor hypersensitivity in mice2020

    • Author(s)
      Tsubota Maho、Matsui Kazuki、Nakano Maki、Kajitani Rie、Ishii Yuko、Tomochika Ken、Nishikawa Yuta、Fukushi Saaya、Yamagata Ayumu、Sekiguchi Fumiko、Okada Takuya、Toyooka Naoki、Kawabata Atsufumi
    • Journal Title

      European Journal of Pharmacology

      Volume: 887 Pages: 173576-173576

    • DOI

      10.1016/j.ejphar.2020.173576

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Tacrolimus, a calcineurin inhibitor, promotes capsaicin-induced colonic pain in mice2020

    • Author(s)
      Matsui Kazuki、Terada Yuka、Tsubota Maho、Sekiguchi Fumiko、Kawabata Atsufumi
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 143 Issue: 1 Pages: 60-63

    • DOI

      10.1016/j.jphs.2020.01.006

    • Related Report
      2020 Annual Research Report 2019 Research-status Report
  • [Journal Article] HMGB1 and its membrane receptors as therapeutic targets in an intravesical substance P-induced bladder pain syndrome mouse model2020

    • Author(s)
      Irie Yuhei、Tsubota Maho、Maeda Mariko、Hiramoto Shiori、Sekiguchi Fumiko、Ishikura Hiroyasu、Wake Hidenori、Nishibori Masahiro、Kawabata Atsufumi
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: in press Issue: 2 Pages: 112-116

    • DOI

      10.1016/j.jphs.2020.03.002

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Role of non-macrophage cell-derived HMGB1 in oxaliplatin-induced peripheral neuropathy and its prevention by the thrombin/thrombomodulin system in rodents: negative impact of anticoagulants2019

    • Author(s)
      Tsubota Maho、Fukuda Ryotaro、Hayashi Yusuke、Miyazaki Takaya、Ueda Shin、Yamashita Rika、Koike Nene、Sekiguchi Fumiko、Wake Hidenori、Wakatsuki Shuji、Ujiie Yuka、Araki Toshiyuki、Nishibori Masahiro、Kawabata Atsufumi
    • Journal Title

      Journal of Neuroinflammation

      Volume: 16 Issue: 1 Pages: 199-199

    • DOI

      10.1186/s12974-019-1581-6

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic deletion of Cav3.2?T-type calcium channels abolishes H2S-dependent somatic and visceral pain signaling in C57BL/6 mice2019

    • Author(s)
      Matsui Kazuki、Tsubota Maho、Fukushi Saaya、Koike Nene、Masuda Hiroshi、Kasanami Yoshihito、Miyazaki Takaya、Sekiguchi Fumiko、Ohkubo Tsuyako、Yoshida Shigeru、Mukai Yutaro、Oita Akira、Takada Mitsutaka、Kawabata Atsufumi
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 140 Issue: 3 Pages: 310-312

    • DOI

      10.1016/j.jphs.2019.07.010

    • Related Report
      2019 Research-status Report
  • [Journal Article] HMGB1 as a target for prevention of chemotherapy-induced peripheral neuropathy2019

    • Author(s)
      Kawabata Atsufumi、Tsubota Maho、Sekiguchi Fumiko、Tsujita Ryuichi
    • Journal Title

      Folia Pharmacologica Japonica

      Volume: 154 Issue: 5 Pages: 236-240

    • DOI

      10.1254/fpj.154.236

    • NAID

      130007745814

    • ISSN
      0015-5691, 1347-8397
    • Related Report
      2019 Research-status Report
  • [Journal Article] Regulation of Ca<sub>v</sub>3.2-mediated pain signals by hydrogen sulfide2019

    • Author(s)
      Tsubota Maho、Kawabata Atsufumi
    • Journal Title

      Folia Pharmacologica Japonica

      Volume: 154 Issue: 3 Pages: 128-132

    • DOI

      10.1254/fpj.154.128

    • NAID

      130007706583

    • Related Report
      2019 Research-status Report
  • [Journal Article] Dietary ascorbic acid restriction in GNL/SMP30-knockout mice unveils the role of ascorbic acid in regulation of somatic and visceral pain sensitivity2019

    • Author(s)
      Tsubota Maho、Uebo Kenta、Miki Koki、Sekiguchi Fumiko、Ishigami Akihiko、Kawabata Atsufumi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 511 Issue: 3 Pages: 705-710

    • DOI

      10.1016/j.bbrc.2019.02.102

    • Related Report
      2019 Research-status Report
  • [Journal Article] NNC 55-0396, a T-type calcium channel blocker, protects against the brain injury induced by middle cerebral artery occlusion and reperfusion in mice2019

    • Author(s)
      Matsuda Sachi、Nishikawa Hiroyuki、Fukatsu Anna、Kurokawa Yuko、Tsubota Maho、Sekiguchi Fumiko、Tokuyama Shogo、Kawabata Atsufumi
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 140 Issue: 2 Pages: 193-196

    • DOI

      10.1016/j.jphs.2019.02.002

    • Related Report
      2019 Research-status Report
  • [Journal Article] Critical role of Cav3.2 T-type calcium channels in the peripheral neuropathy induced by bortezomib, a proteasome-inhibiting chemotherapeutic agent, in mice2019

    • Author(s)
      Tomita Shiori、Sekiguchi Fumiko、Deguchi Tomoyo、Miyazaki Takaya、Ikeda Yuya、Tsubota Maho、Yoshida Shigeru、Nguyen Huy Du、Okada Takuya、Toyooka Naoki、Kawabata Atsufumi
    • Journal Title

      Toxicology

      Volume: 413 Pages: 33-39

    • DOI

      10.1016/j.tox.2018.12.003

    • Related Report
      2019 Research-status Report
  • [Presentation] 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2021

    • Author(s)
      山縣歩夢、松井和樹、坪田真帆、西堀正洋、川畑篤史
    • Organizer
      第94回日本薬理学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 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2020

    • Author(s)
      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
    • Organizer
      第138回日本薬理学会近畿部会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Middle molecular weight heparinylphenylalanine selectively blocks RAGE and reduces HMGB1-dependent neuropathic and visceral pain in mice.2020

    • Author(s)
      Kawabata, A., Nishikawa, H. Higashimoto, K., Uenoyama, K., Sekiguchi, F., Tsubota, M., Okada, T., Toyooka, N
    • Organizer
      12th FENS Forum of Neuroscience
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 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2019

    • Author(s)
      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
    • Organizer
      第69回日本薬学会関西支部総会・大会
    • Related Report
      2019 Research-status Report
  • [Presentation] 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2019

    • Author(s)
      山縣歩夢、松井和樹、坪田真帆、川畑篤史
    • Organizer
      第69回日本薬学会関西支部総会・大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Dietary ascorbic acid restriction in GNL/SMP30-knockout mice unveils the role of ascorbic acid in regulation of Cav3.2-dependent pain.2019

    • Author(s)
      Kawabata, A., Tsubota, M., Uebo, K., Miki, K., Sekiguchi, F., Ishigami, A.
    • Organizer
      11th Congress of the European Pain Federation EFIC (2019 Pain in Europe XI),
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 6-Prenylnaringenin and its derivative, KTt45, are mixed T-type Ca2+ channel inhibitors/CB2 receptor agonists: antinociceptive activity in neuropathic and visceral pain models.2019

    • Author(s)
      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.
    • Organizer
      11th Congress of the European Pain Federation EFIC (2019 Pain in Europe XI),
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Critical role of Cav3.2 T-type calcium channels in H2S-dependent somatic and visceral pain signaling in mice.2019

    • Author(s)
      Matsui, K., Fukushi, S., Koike, N., Yamagata, A., Tsubota, M., Mukai, Y., Oita, A., Takada, M., Kawabata, A.
    • Organizer
      11th Congress of the European Pain Federation EFIC (2019 Pain in Europe XI),
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Crosstalk between the HMGB1/RAGE and CSE/H2S/Cav3.2 pathways involved in cystitis-related bladder pain in mice.2019

    • Author(s)
      Hiramoto, S., Tsubota, M., Yamaguchi, K., Okazaki, K., Tanaka, J., Sekiguchi, F., Ishikura, H., Nishibori, M., Kawabata, A.
    • Organizer
      11th Congress of the European Pain Federation EFIC (2019 Pain in Europe XI),
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 硫化水素によるCav3.2を介する疼痛シグナルの調節.2019

    • Author(s)
      坪田真帆、川畑篤史.
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 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.2019

    • Author(s)
      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.
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 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.2019

    • Author(s)
      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.
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 硫化水素によるCav3.2を介する疼痛シグナルの調節2019

    • Author(s)
      坪田真帆、川畑篤史
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] 内臓痛発現における硫化水素および過硫化物の役割2018

    • Author(s)
      坪田真帆、川畑篤史
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] Pharmacological blockade and genetic deletion of Cav3.2 T-type Ca2+ channels abolish butyrate-induced colonic hypersensitivity in mice2018

    • Author(s)
      Matsui, K., Nakano, M., Tomochika, K., Tsubota, M., Kawabata, A
    • Organizer
      17th World Congress on Pain
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Role of Cav3.2 T-type calcium channels in the butyrate-induced colonic hypersensitivity in the mouse, a model for irritable bowel syndrome2018

    • Author(s)
      Tsubota, M., Matsui, K., Nakano, M. Tomochika, K., Sekiguchi, F., Kawabata, A
    • Organizer
      10th International Symposium on Cell/Tissue Injury and Cytoprotection/Organoprotection.
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 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2018

    • Author(s)
      坪田真帆、松井和樹、中野真希、友近拳、関口富美子、川畑篤史
    • Organizer
      第133回日本薬理学会近畿部会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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