Regulation of brain inflammation, a causative factor in Alzheimer's disease, by natural retinoid X receptor agonists

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06636
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47050:Environmental and natural pharmaceutical resources-related
• Research Institution: Aichi Gakuin University
• Principal Investigator: Inoue Makoto 愛知学院大学, 薬学部, 教授 (50191888)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: retinoid X receptor / RXR agonist / nuclear receptor / Alzheimer's disease / microglia / inflammation / adverse effect

Outline of Final Research Achievements

Currently, there are no effective therapeutic drugs available for Alzheimer's disease (AD) dementia. In this study, we focused on retinoid X receptor (RXR) agonists, which have been suggested to be effective but have not progressed as drug candidates due to side effects and other issues. Specifically, we investigated the biological characteristics of 6OHA, an RXR agonist developed in our laboratory. 6OHA exhibited both early-stage anti-inflammatory effects and inflammation resolution-promoting effects on microglial inflammation, indicating its potential to suppress brain inflammation, a primary cause of AD onset. Additionally, 6OHA demonstrated high bioavailability and did not exhibit common side effects associated with RXR agonists, such as hypertriglyceridemia and hypothyroidism, establishing it as a promising and safe candidate compound for AD treatment.

Free Research Field

Pharmaceutical Sciences

Academic Significance and Societal Importance of the Research Achievements

本研究では、新規RXRアゴニスト6OHAが抗炎症作用と炎症収束促進作用を有する可能性を見出し、生物学的利用能の高さを考慮すると、ADの主原因と考えられるようになってきた脳内炎症を効果的に抑制できるRXRアゴニストである可能性が示唆された。また、6OHAはこれまでに開発されたRXRアゴニストに頻繁に観察された高TG血症、甲状腺機能低下症などの副作用を示さないRXRアゴニストとして、AD治療薬候補として非常に有望であることを示唆する結果を多く明らかにすることができた。今後、6OHAがAD治療薬として臨床で応用できるような研究を進め、社会実装できることを期待している。