Evodiamine derivatives improve cognitive abilities in APPswe/PS1ΔE9 transgenic mouse models of Alzheimer's disease

Shuo Pang; Caixian Sun; Shan Gao; Yajun Yang; Xiandao Pan; Lianfeng Zhang

doi:10.1002/ame2.12126

Evodiamine derivatives improve cognitive abilities in APP^swe/PS1^ΔE9 transgenic mouse models of Alzheimer's disease

Animal Model Exp Med. 2020 Jun 29;3(2):193-199. doi: 10.1002/ame2.12126. eCollection 2020 Jun.

Authors

Shuo Pang^{1

2}, Caixian Sun^{1

2}, Shan Gao^{1

2}, Yajun Yang³, Xiandao Pan³, Lianfeng Zhang^{1

2

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

Background: Alzheimer's disease (AD) is a complex neurodegenerative disease. Due to the complexity of its molecular pathogenesis and the interaction of the numerous factors involved, the etiology and pathogenesis of AD have not been fully elucidated. Therefore, effective treatment for AD remains to be developed. Evodiamine, a quinolone alkaloid, has been found to improve learning and memory ability to in the APP^swe/PS1^△E9 mouse model of dementia. However, the cytotoxicity and physicochemical properties of evodiamine have limited its use in the treatment of AD.

Methods: Evodiamine and its derivatives were effectively synthesized by EDCI-mediated condensation at room temperature. These target compounds contained 1 thio- and 21 oxo-evodiamine derivatives with different substituted groups. The cytotoxicity of evodiamine and its derivatives and the neuroprotective effects of the evodiamine derivatives against H₂O₂-induced cell loss in SH-SY5Y cells were investigated using the WST-8 assay. The Morris water-maze test was used to detect the effect of evodiamine and its derivatives on improving learning and memory in APP^swe/PS1^△E9 mice.

Results: In this study, a series of oxo- and thio-evodiamine derivatives was synthesized. Several derivatives showed lower cytotoxicity and stronger neuroprotective effects than evodiamine and elicited enhanced cognitive improvement, especially in the test of spatial memory in APP^swe/PS1^△E9 mice.

Conclusion: Our study provides insights for developing novel evodiamine derivatives for chemical intervention and treatment of AD.

Keywords: evodiamine derivatives; mouse model; neuroprotective; spatial memory.