首页|FO-4-15,a novel 1,2,4-oxadiazole derivative,ameliorates cognitive impairments in 3×Tg mice by activating the mGluR1/CaMKⅡα pathway

FO-4-15,a novel 1,2,4-oxadiazole derivative,ameliorates cognitive impairments in 3×Tg mice by activating the mGluR1/CaMKⅡα pathway

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FO-4-15,a novel 1,2,4-oxadiazole derivative,ameliorates cognitive impairments in 3×Tg mice by activating the mGluR1/CaMKⅡα pathway
Alzheimer's disease(AD)is the most prevalent neurodegenerative disorder characterized by cognitive impairments.Despite the limited efficacy of current treatments for AD,the 1,2,4-oxadiazole structure has garnered significant attention in medicinal chemistry due to its potential impact on mGluR1 and its association with AD therapy.In this study,a series of novel 1,2,4-oxadiazole derivatives were designed,synthesized,and evaluated for the neuroprotective effects in human neuroblastoma(SH-SY5Y)cells.Among all the derivatives tested,FO-4-15(5f)existed the lowest cytotoxicity and the highest protective effect against H2O2.Based on these in vitro results,FO-4-15 was administered to 3×Tg mice and significantly improved the cognitive impairments of the AD mice.Pathological analysis showed that FO-4-15 significantly reduced Aβ accumulation,Tau hyper-phosphorylation,and synaptic impairments in the 3×Tg mice.Dysfunction of the CaMKⅡα/Fos signaling pathway in 3×Tg mice was found to be restored by FO-4-15 and the necessity of the CaMKⅡα/Fos for FO-4-15 was subsequently confirmed by the use of a CaMKⅡα inhibitor in vitro.Beyond that,mGluR1 was identified to be a potential target of FO-4-15,and the interaction of FO-4-15 and mGluR1 was displayed by Ca2+flow increase,molecular docking,and interaction energy analysis.The target of FO-4-15 was further confirmed in vitro by JNJ16259685,a nonselective inhibitor of mGluR1.These findings suggest that FO-4-15 may hold promise as a potential treatment for Alzheimer's disease.

Alzheimer's disease1,2,4-oxadiazole3×Tg miceCaMKⅡα/Fos pathwayneuroprotective effectneuroplasticity

Zhuo-hui Luo、Jiang-shan Guo、Shuo Pang、Wei Dong、Jia-xin Ma、Li Zhang、Xiao-long Qi、Fei-fei Guan、Shan Gao、Xiang Gao、Ning Liu、Shuo Pan、Wei Chen、Xu Zhang、Lian-feng Zhang、Ya-jun Yang

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Key Laboratory of Human Disease Comparative Medicine,National Health Commission of China,Institute of Laboratory Animal Science,Peking Union Medical College,Chinese Academy of Medical Sciences,Beijing 100021,China

Beijing Key Laboratory of Active Substance Discovery and Drug Ability Evaluation,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China

The Laboratory of Neurological Disorders and Brain Cognition,Beijing Pediatric Research Institute,Beijing Children's Hospital,Capital Medical University,National Center for Children's Health,Beijing 100045,China

Beijing Engineering Research Center for Experimental Animal Models of Human Diseases,Institute of Laboratory Animal Science,Peking Union Medical College,Chinese Academy of Medical Sciences,Beijing 100021,China

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Alzheimer's disease 1,2,4-oxadiazole 3×Tg mice CaMKⅡα/Fos pathway neuroprotective effect neuroplasticity

2025

10.1038/s41401-024-01362-0

中国药理学报(英文版)
中科院上海药物研究所

中国药理学报(英文版)

影响因子：0.926
ISSN：1671-4083
年,卷(期)：2025.46(1)