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

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

doi:10.3389/fnmol.2022.1025066

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

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

Authors

Shuo Pang^{1

2}, Siyuan Li³, Hanzeng Cheng³, Zhuohui Luo^{1

2}, Xiaolong Qi^{1

2}, Feifei Guan^{1

2}, Wei Dong¹, Shan Gao¹, Ning Liu², Xiang Gao², Shuo Pan², Xu Zhang², Li Zhang^{1

2}, Yajun Yang³, Lianfeng Zhang^{1

4}

Affiliations

¹ 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.
² 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.
³ Beijing Key Laboratory of Active Substance Discovery and Drug Ability Evaluation, Institute of Material Medical, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁴ Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China.

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 via heterocyclic substitution and amide introduction and screened for cytotoxicity and antioxidant capacity. Under the same concentrations, compound 4c was found to exhibit lower cytotoxicity and higher activity against H₂O₂ and amyloid β oligomers (AβOs) than evodiamine in vitro 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 4c affected AD-related genes and the AMPK and insulin signaling pathways. Furthermore, we confirmed that 4c recovered PI3K/AKT/GSK3β/Tau dysfunction in vivo and in vitro. In conclusion, 4c represents a potential lead compound for AD therapy based on the recovery of PI3K/AKT/GSK3β pathway dysfunction.

Keywords: Alzheimer's disease; Aβ pathology; PI3K/AKT/GSK3β pathway; Tau hyperphosphorylation; evodiamine.

Grants and funding

This study was supported by the National Key Research and Development Program of China (2022YFF0710702), the National Natural Science Foundation of China (grant no. 31970508), the CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-1-034), and the Drug Innovation Major Project (2018ZX09711-001-005).