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

• Project/Area Number: 18K06710
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Kindai 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: ¥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。

Research Products

• [Journal Article] Effects of Bepridil and Pimozide, Existing Medicines Capable of Blocking T-Type Ca²⁺ Channels, on Visceral Pain in Mice (2021)
  • 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
  • Peer Reviewed
• [Journal Article] Essential role of Cav3.2 T-type calcium channels in butyrate-induced colonic pain and nociceptor hypersensitivity in mice (2020)
  • 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
  • Peer Reviewed
• [Journal Article] Tacrolimus, a calcineurin inhibitor, promotes capsaicin-induced colonic pain in mice (2020)
  • 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
• [Journal Article] HMGB1 and its membrane receptors as therapeutic targets in an intravesical substance P-induced bladder pain syndrome mouse model (2020)
  • 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
  • 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 anticoagulants (2019)
  • 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
  • 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 mice (2019)
  • 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
• [Journal Article] HMGB1 as a target for prevention of chemotherapy-induced peripheral neuropathy (2019)
  • 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
• [Journal Article] Regulation of Ca_v3.2-mediated pain signals by hydrogen sulfide (2019)
  • 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
• [Journal Article] Dietary ascorbic acid restriction in GNL/SMP30-knockout mice unveils the role of ascorbic acid in regulation of somatic and visceral pain sensitivity (2019)
  • 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
• [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 mice (2019)
  • 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
• [Journal Article] Critical role of Cav3.2 T-type calcium channels in the peripheral neuropathy induced by bortezomib, a proteasome-inhibiting chemotherapeutic agent, in mice (2019)
  • 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
• [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
• [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
• [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
  • 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
• [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
• [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),
  • 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),
  • 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),
  • 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),
  • 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
• [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
• [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
• [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
• [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
• [Presentation] Pharmacological blockade and genetic deletion of Cav3.2 T-type Ca2+ channels abolish butyrate-induced colonic hypersensitivity in mice (2018)
  • Author(s): Matsui, K., Nakano, M., Tomochika, K., Tsubota, M., Kawabata, A
  • Organizer: 17th World Congress on Pain
  • 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 syndrome (2018)
  • 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.
  • 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