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在小鼠模型中发现一种用于激活PI3K/AKT/GSK3β通路及改善阿尔茨海默病病理学的吴茱萸碱衍生物。

Discovery of an evodiamine derivative for PI3K/AKT/GSK3β pathway activation and AD pathology improvement in mouse models.

作者信息

Pang Shuo, Li Siyuan, Cheng Hanzeng, Luo Zhuohui, Qi Xiaolong, Guan Feifei, Dong Wei, Gao Shan, Liu Ning, Gao Xiang, Pan Shuo, Zhang Xu, Zhang Li, Yang Yajun, Zhang Lianfeng

机构信息

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

出版信息

Front Mol Neurosci. 2023 Jan 9;15:1025066. doi: 10.3389/fnmol.2022.1025066. eCollection 2022.

DOI:10.3389/fnmol.2022.1025066
PMID:36698780
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9868638/
Abstract

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive neurodegeneration and cognitive decline. Evodiamine, a main component in Chinese medicine, was found to improve cognitive impairment in AD model mice based on several intensive studies. However, evodiamine has high cytotoxicity and poor bioactivity. In this study, several evodiamine derivatives were synthesized heterocyclic substitution and amide introduction and screened for cytotoxicity and antioxidant capacity. Under the same concentrations, compound was found to exhibit lower cytotoxicity and higher activity against HO and amyloid β oligomers (AβOs) than evodiamine and significantly improve the working memory and spatial memory of 3 x Tg and APP/PS1 AD mice. Subsequent RNA sequencing and pathway enrichment analysis showed that affected AD-related genes and the AMPK and insulin signaling pathways. Furthermore, we confirmed that recovered PI3K/AKT/GSK3β/Tau dysfunction and . In conclusion, represents a potential lead compound for AD therapy based on the recovery of PI3K/AKT/GSK3β pathway dysfunction.

摘要

阿尔茨海默病（AD）是一种以进行性神经退行性变和认知衰退为特征的神经退行性疾病。基于多项深入研究发现，中药中的主要成分吴茱萸碱可改善AD模型小鼠的认知障碍。然而，吴茱萸碱具有高细胞毒性和低生物活性。在本研究中，通过杂环取代和引入酰胺合成了几种吴茱萸碱衍生物，并对其细胞毒性和抗氧化能力进行了筛选。在相同浓度下，发现化合物 比吴茱萸碱表现出更低的细胞毒性和更高的抗HO和淀粉样β寡聚体（AβOs）活性，并显著改善3xTg和APP/PS1 AD小鼠的工作记忆和空间记忆。随后的RNA测序和通路富集分析表明， 影响与AD相关的基因以及AMPK和胰岛素信号通路。此外，我们证实 恢复了PI3K/AKT/GSK3β/Tau功能障碍 以及 。总之，基于PI3K/AKT/GSK3β通路功能障碍的恢复， 代表了一种潜在的AD治疗先导化合物。

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