PACAP-PAC1 signal-targeted drug development for stress-induced disorders

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07121
• 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: Osaka University
• Principal Investigator: Hayata-Takano Atsuko 大阪大学, 大学院歯学研究科, 准教授 (70390812)
• Co-Investigator(Kenkyū-buntansha): 橋本 均 大阪大学, 大学院薬学研究科, 教授 (30240849)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: PACAP / 精神疾患 / ストレス

Outline of Final Research Achievements

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved pleiotropic neuropeptide, implicated in emotional stress responses and anxiety-related disorders. We recently developed novel small-molecule non-peptide antagonists of the PACAP receptor (PAC1) using docking-based in silico screening. In the present study, we aimed to examine the effects of the PAC1 antagonists on acute emotional stress-induced anxiety-like behaviors or repeated social defeat stress (RSDS)-induced depression-like behaviors.
The antagonists significantly improved anxiety-like behaviors in mice subjected to acute restraint stress. A single dose of the antagonist significantly ameliorated depression-like behaviors in RSDS mice, and this effect lasted 8 weeks. The antagonist also attenuated anxiety-like behaviors and cognitive deficits in RSDS mice. These results suggest that our novel PAC1 antagonist would be a new class of antidepressant with strong efficacy and high safety profile.

Free Research Field

神経分子薬理学

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、治療満足度や寛解率が十分ではないうつ病や不安障害などの精神疾患の既存薬とは異なる作用機序をもつPACAP受容体アンタゴニストが、単回投与することで即効性かつ持続的な抗うつ・抗不安作用や記憶障害の改善を示すものである。このことは、本拮抗薬が不安障害・うつ病に対して、安全で有効な新規治療薬の候補となることを示している。また、本研究の成果は、ストレス関連性精神疾患の病態解明や、さらなる治療薬の開発の手がかりを得ることにも繋がるものであり、その学術的意義は極めて高いと考えられる。