Development of novel therapeutic drugs for traumatic brain injury focused on functional molecules in astrocytes

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K16016
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Meiji Pharmaceutical University (2021-2022); Osaka Ohtani University (2020)
• Principal Investigator: Michinaga Shotaro 明治薬科大学, 薬学部, 講師 (60624054)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: アストロサイト / 頭部外傷 / 血液脳関門 / 脳浮腫

Outline of Final Research Achievements

In the injured cerebrum of traumatic brain injury (TBI) model mice, we found that endothelin ETB receptor, transient receptor potential vanilloid 4 (TRPV4), histamine H2 receptor were predominantly expressed in reactive astrocytes. We also showed that repeated administrations of ETB receptor antagonist, TRPV4 antagonist, and H2 receptor agonist alleviated the BBB disruption and brain edema in TBI model mice. Furthermore, these drugs decreased expression level of astrocyte-derived promoting factors for the BBB disruption and increased expression level of astrocyte-derived protective factors in the injured cerebrum after TBI. These results suggest that ETB receptor, TRPV4, and H2 receptor are functional molecules for regulating astrocyte functions and these astrocytic functional molecules are attractive candidates for developing therapeutic drugs to TBI.

Free Research Field

中枢神経薬理

Academic Significance and Societal Importance of the Research Achievements

頭部外傷は交通事故、転倒、スポーツなどの際に頭部を強打することで脳が損傷した状態であり、突然死や後遺症を伴う場合もある。日本の患者数は年間30万人以上と推定されているが、現在までに有効な治療薬は確立されていない。本研究成果により、エンドセリンETB受容体拮抗薬、TRPV4阻害薬、ヒスタミンH2受容体作用薬が頭部外傷モデルマウスの病態を抑制できることが示唆されたため、これらの薬は頭部外傷に対する新規治療薬の候補となり得ることが期待される。