2022 Fiscal Year Final Research Report

Genomic analysis-based neuropharmacological study on basal ganglia-thalamocortical circuits for new drug discovery in schizophrenia

Research Project

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Project/Area Number	20H03428
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 48030:Pharmacology-related
Research Institution	Nagoya University
Principal Investigator	Yamada Kiyofumi 名古屋大学, 医学部附属病院, 教授 (30303639)
Co-Investigator(Kenkyū-buntansha)	永井拓藤田医科大学, 精神・神経病態解明センター, 教授 (10377426) 溝口博之名古屋大学, 医学部附属病院, 准教授 (70402568)
Project Period (FY)	2020-04-01 – 2023-03-31
Keywords	統合失調症 / Rhoキナーゼ / 抗精神病作用 / Fasudil
Outline of Final Research Achievements	We have generated a disease model mouse with ARHGAP10 gene mutation identified in a Japanese schizophrenia (SCZ) patient and identified Rho kinase as a novel therapeutic target by phenotypic analysis. In order to elucidate the role of Rho kinase in the regulation of higher brain functions, we performed pharmacologic functional analysis with fasudil, a non-selective ROCK inhibitor, and KD025, a selective ROCK2 inhibitor in this study. We also analyzed the effects of ROCK inhibitors on neuronal activity in striatal dopamine D1 receptor-expressing medium spiny neurons (DIR-MSN) in which GCaMP has been expressed with AAV expression vector. Furthermore, the effects of Fasudil and KD025 on depolarization-evoked dopamine (DA) and serotonin (5HT) release in the nucleus accumbens were analyzed using an in vivo dialysis system. Our findings suggest that ROCK2 could be a better drug target for developing novel antipsychotics.
Free Research Field	薬理学
Academic Significance and Societal Importance of the Research Achievements	SCZは思春期以降に発症する代表的な精神疾患である。有病率は約1%であり、本邦の患者数は79.5万人、その内18.7万人は入院治療を受けており、経済的損失は、間接的費用を含めると年間2.8兆円に達する。SCZの病因・病態は未解明であり、その治療は抗精神病薬を用いた対症療法が中心であるが、十分な薬物治療をしても約2/3の患者には精神障害が残存し、再発・再燃を繰り返す。したがって、従来の抗精神病薬の延長線上ではない、真に有効な治療薬の開発は患者・家族だけでなく社会的要請である。本研究成果は、新規抗精神病薬の開発のための創薬標的としてROCK2を同定した。