Efficacy of temperature-sensitive TRPM8 channels in refractory epilepsy and the elucidation of pathogenetic regulation

• Project/Area Number: 21K15269
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Yamaguchi University
• Principal Investigator: Moriyama Hiroshi 山口大学, 医学部附属病院, 助教 (40816633)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2022: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2021: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: てんかん / 脳波 / TRPM8KO / TRPM8作動薬 / 細胞外グルタミン酸 / てんかん発作 / てんかん性異常脳波 / マウス / TRPM8チャネル / 細胞外グルタミン酸濃度 / パッチクランプ / 薬剤誘発性てんかんモデル / 温度感受性受容体 / 難治性てんかん / TRPM8

Outline of Research at the Start

既存の抗てんかん薬でコントロール不良な難治性てんかん患者はてんかん患者全体の約3割と多い．そこで我々は，脳を直接冷やす局所脳冷却技術を開発し，難治性てんかんに対する有効性を示したが，局所脳冷却処置は侵襲性が高く，臨床応用には至っていない．これらの背景から，本研究では局所脳冷却技術を薬剤で代替可能か検討する．その候補が冷却温度（15℃）で活性化するTRPM8チャネルである．
本研究では，難治性てんかん患者に対する新規作用機序に基づく抗てんかん薬の開発を大目的として，TRPM8チャネルの抗てんかん作用をマウスのてんかん焦点及び細胞単位で調べ，TRPM8チャネルによるてんかんの病態制御基盤を解明する．

Outline of Final Research Achievements

We hypothesized that drug-induced activation of a temperature-sensitive Transient Receptor Potential Melastatin 8 (TRPM8) channel would suppress epileptic seizures in mice and conducted this study. The results showed that TRPM8 channel activators suppressed drug-induced epileptic seizures in wild type mice. In contrast, TRPM8 channel activators did not affect drug-induced epileptic seizures in TRPM8 deficient mice. In addition, we compared the epileptic seizures in TRPM8 deficient mice with wild type mice. TRPM8 deficient resulted in a shorter firing latency of epileptic discharges, and epileptic seizures to worsen. The cause was an increase in the extracellular concentration of glutamate which is one of the responsible for epileptic seizures.

Academic Significance and Societal Importance of the Research Achievements

TRPM8チャネルの活性剤がてんかん治療薬の候補であることがわかった．既存の抗てんかん薬と異なる作用機序の解明ができたため薬剤抵抗性を示す難治性てんかん患者への応用が期待される．

Research Products

• [Journal Article] Suppressive effects of a transient receptor potential melastatin 8 (TRPM8) agonist on hyperthermia-induced febrile seizures in infant mice (2023)
  • Author(s): Moriyama Hiroshi、Nomura Sadahiro、Imoto Hirochika、Oka Fumiaki、Maruta Yuichi、Mori Naomasa、Fujii Natsumi、Suzuki Michiyasu、Ishihara Hideyuki
  • Journal Title: Frontiers in Pharmacology Volume: 14 Pages: 1-9
  • DOI: 10.3389/fphar.2023.1138673
  • Peer Reviewed / Open Access
• [Journal Article] Sansoninto attenuates aggressive behavior and increases levels of homovanillic acid, a dopamine metabolite, in social isolation-reared mice (2022)
  • Author(s): Watanabe Takuya、Iba Hikari、Moriyama Hiroshi、Kubota Kaori、Katsurabayashi Shutaro、Iwasaki Katsunori
  • Journal Title: Journal of Traditional and Complementary Medicine Volume: 12 Issue: 3 Pages: 243-249
  • DOI: 10.1016/j.jtcme.2021.08.006
  • Peer Reviewed / Open Access
• [Journal Article] Suppressive Effects of Transient Receptor Potential Melastatin 8 Agonist on Epileptiform Discharges and Epileptic Seizures. (2021)
  • Author(s): Moriyama H, Nomura S, Imoto H, Inoue T, Fujiyama Y, Haji K, Maruta Y, Ishihara H, Suzuki M.
  • Journal Title: Front Pharmacol. Volume: 12 Pages: 766-782
  • DOI: 10.3389/fphar.2021.766782
  • Peer Reviewed / Open Access
• [Presentation] 細胞外グルタミン酸濃度調節を介したTRPM8チャネルの抗てんかん作用 (2021)
  • Author(s): 森山 博史、野村 貞宏、井本 浩哉、丸田 雄一、土師 康平、井上 貴雄、鈴木 倫保、石原 秀行
  • Organizer: 第54回日本てんかん学会学術集会