AUTHOR=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 

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

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=15

YEAR=2023

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2022.1025066

DOI=10.3389/fnmol.2022.1025066

ISSN=1662-5099

ABSTRACT=<p>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 <italic>via</italic> heterocyclic substitution and amide introduction and screened for cytotoxicity and antioxidant capacity. Under the same concentrations, compound <bold>4c</bold> was found to exhibit lower cytotoxicity and higher activity against H<sub>2</sub>O<sub>2</sub> and amyloid β oligomers (AβOs) than evodiamine <italic>in vitro</italic> 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 <bold>4c</bold> affected AD-related genes and the AMPK and insulin signaling pathways. Furthermore, we confirmed that <bold>4c</bold> recovered PI3K/AKT/GSK3β/Tau dysfunction <italic>in vivo</italic> and <italic>in vitro</italic>. In conclusion, <bold>4c</bold> represents a potential lead compound for AD therapy based on the recovery of PI3K/AKT/GSK3β pathway dysfunction.</p>