The role of T-type calcium channel in the neurotoxicity of local anesthetics

• Project/Area Number: 17K11065
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Anesthesiology
• Research Institution: Aichi Medical University
• Principal Investigator: FUJIWARA YOSHIHIRO 愛知医科大学, 医学部, 教授 (70238640)
• Co-Investigator(Kenkyū-buntansha): 馮 国剛 愛知医科大学, 医学部, 講師 (70351111)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: ブピバカイン / アポトーシス / T型カルシウムチャネル / 活性酸素 / ミトコンドリア / 神経毒性 / 局所麻酔薬 / カルシウムチャネル / 薬理学 / イオンチャンネル

Outline of Final Research Achievements

Bupivacaine produced cytotoxicity in SH-SY5Y cells in dose and time dependent manner. T-type calcium channel antagonist, NNC55-0396 markedly enhanced cytotoxic effect of bupivacaine. Apoptosis induced by bupivacaine was associated with induction of caspase-3, depolarization of mitchondrial membrane and increase in intracellular reactive oxygen spiecies.

Academic Significance and Societal Importance of the Research Achievements

局所麻酔薬の潜在的神経毒性は脊髄くも膜下麻酔後の馬尾症候群や神経ブロック後の神経障害の原因と考えられており，早急に解決されるべき問題である。本研究では神経細胞に対するブピバカインのアポトーシス誘導作用の機序についていくつかの新しい知見を得ることができた。これらの結果は今後局所麻酔薬の神経毒性作用を抑制する方策を探求するうえで極めて有用であると考えている。

Research Products

• [Presentation] Diazoxide, ATP-sensitive potassium channel opener, does not affect the neurotoxicity of bupivacaine. (2019)
  • Author(s): Ishihara R, Tanaka K, Fujiwara Y
  • Organizer: International Symposium on Ultrasound Regional Anesthesia
  • Int'l Joint Research
• [Presentation] Diazoxide, ATP-sensitive potassium channel opener, does not affect the neurotoxicity of bupivacaine (2019)
  • Author(s): Ishihara R, Tanaka K, Fujiwara Y
  • Organizer: International Symposium of Ultrasound for Regional Anesthesia and Pain Medicine 2019
  • Int'l Joint Research
• [Presentation] Bupivacaine induces apoptosis via blocking T-type Ca2+ channels and resulting activation of mitochondrial apoptotic pathway in SH-SY5Y cells. (2018)
  • Author(s): Fujiwara Y, Tanaka K, Tetsu S, Ishihara R, Aoyama H, Niwa H
  • Organizer: Euroanaesthesia 2018
  • Int'l Joint Research
• [Presentation] Bupivacaine induces apoptosis via blocking T-type Ca2+ channels and resulting activation of mitochondrial apoptotic pathway in SH-SY5Y cells (2018)
  • Author(s): Yoshihiro Fujiwara
  • Organizer: Euroanaeshtesia 2018
  • Int'l Joint Research
• [Presentation] Bupivacaine induces apoptosis via inhibiting T-type Ca 2+ channels in SH-SY5Y cells. (2017)
  • Author(s): Tanaka K
  • Organizer: Annual Meeting of American Society Anesthesiologists 2017
  • Int'l Joint Research