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

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.

Therapeutic Effects of the major alkaloid constituents of Evodia rutaecarpa in Alzheimer's disease

“…Furthermore, recent studies have demonstrated that evodiamine derivatives can activate the phosphoinositide 3‐kinase / protein kinase B / glycogen synthase kinase 3β (PI3K/AKT/GSK3β) pathway, exerting their activity against H 2 O 2 and Aβ oligomers (AβOs). This activity significantly improves working memory and spatial memory in 3xTg and amyloid precursor protein (APP)/PS1 transgenic mice 14 . These findings suggest the potential therapeutic effect of evodiamine in AD.…”

“…This activity significantly improves working memory and spatial memory in 3xTg and amyloid precursor protein (APP)/PS1 transgenic mice. 14 These findings suggest the potential therapeutic effect of evodiamine in AD.…”

Enhancing apoptosis-mediated anticancer activity of evodiamine through protein-based nanoparticles in breast cancer cells

“…Evodiamine (EVO) is an indolequinone alkaloid derived from Evodia rutaecarpa 5 . EVO is composed of a pentacyclic structure including three nitrogen atoms and exhibits abundant pharmacological potential including anti-cancer 6 , anti-bacterial 7 , and anti-neurodegenerative 8 , anti-inflammatory 9 , anti-obesity 10 , anti-depressant 11 and cardioprotective 12 . Furthermore, reported studies demonstrated that it has a promising anticancer property by specifically inducing apoptosis and cell cycle arrest, reducing cell proliferation and inhibiting metastasis in cancer cells 13 – 15 .…”

Effect of acupuncture on neuroinflammation in animal models of Alzheimer’s disease: A preclinical systematic review and meta-analysis

“…International research on traditional Chinese medicine for the treatment of AD has focused on Chinese herbs [e.g., Morinda officinalis How , Astragali radix (Dong et al, 2022)] or active ingredients of Chinese herbs [e.g., polysaccharides , ginsenoside (Wu et al, 2022a), evodiamine (Pang et al, 2022), Huperzine A (Yan et al, 2022)], herbal prescriptions [e.g., Yi-Gan San (Yang et al, 2023), Yuan-Zhi Decoction (Wu et al, 2022b)], special therapies [e.g., Wuqinxi exercise (Luo et al, 2022), Tai Chi Quan (Wang et al, 2022)], and acupuncture (Cai et al, 2019;Yu et al, 2021a;Zheng et al, 2021;Hao et al, 2022) to improve memory and cognitive impairment in AD models, involving various mechanisms such as regulation of βamyloid and tau proteins, anti-oxidation, anti-neuroinflammation, modulation of autophagy and many other mechanisms. Among these, acupuncture is considered to be a highly promising alternative therapy for AD.…”