Mechanisms underlying the antidepressant-like effects of intranasal administration of resolvins in animal models of depression and treatment-resistant depression

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07120
• 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: Kanazawa University
• Principal Investigator: Deyama Satoshi 金沢大学, 薬学系, 准教授 (30634993)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: レゾルビン / ω-3不飽和脂肪酸 / 抗うつ薬 / うつ病 / 治療抵抗性うつ病 / 内側前頭前野 / mTORC1

Outline of Final Research Achievements

In this study, we found that intranasal (i.n.) administration of resolvin E1 (RvE1), a bioactive lipid mediator derived from EPA, produces antidepressant-like effects via BDNF/VEGF release and the subsequent activation of mTORC1 in the medial prefrontal cortex (mPFC) in mouse models of depression, including a treatment-resistant depression model. We also found that intraperitoneal and oral administration of o-BZ-RvE2, a metabolically stable analog of resolvin E2, an EPA metabolite, produces antidepressant-like effects via mTORC1 activation in the mPFC. These findings suggest that i.n. administration is a viable and promising route for the delivery of unstable resolvins to the brain and can pave the way for the application of resolvins in the treatment of depression. Moreover, this study suggests that stable resolvin analogs could be lead compounds for novel antidepressants.

Free Research Field

神経薬理学

Academic Significance and Societal Importance of the Research Achievements

うつ病の患者数は世界で約2.8億人と言われ、深刻な社会的・経済的損失をもたらしている。一方、既存の抗うつ薬は効果発現が遅く、3割の患者が治療抵抗性を示すため、新たな抗うつ薬の開発が喫緊の課題である。本研究の成果により、レゾルビン類やその誘導体が新たな抗うつ薬候補化合物として有望であることが示唆された。