Pang Shuo, Sun Caixian, Gao Shan, Yang Yajun, Pan Xiandao, Zhang Lianfeng
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.
Animal Model Exp Med. 2020 Jun 29;3(2):193-199. doi: 10.1002/ame2.12126. eCollection 2020 Jun.
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/PS1 mouse model of dementia. However, the cytotoxicity and physicochemical properties of evodiamine have limited its use in the treatment of AD.
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 HO-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/PS1 mice.
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/PS1 mice.
Our study provides insights for developing novel evodiamine derivatives for chemical intervention and treatment of AD.
阿尔茨海默病（AD）是一种复杂的神经退行性疾病。由于其分子发病机制的复杂性以及众多相关因素的相互作用，AD的病因和发病机制尚未完全阐明。因此，仍有待开发针对AD的有效治疗方法。吴茱萸碱是一种喹诺酮生物碱，已发现在APP/PS1痴呆小鼠模型中可改善学习和记忆能力。然而，吴茱萸碱的细胞毒性和理化性质限制了其在AD治疗中的应用。
通过EDCI介导的室温缩合反应有效合成了吴茱萸碱及其衍生物。这些目标化合物包含具有不同取代基的1-硫代-和21-氧代-吴茱萸碱衍生物。使用WST-8法研究了吴茱萸碱及其衍生物的细胞毒性以及吴茱萸碱衍生物对SH-SY5Y细胞中HO诱导的细胞损失的神经保护作用。采用莫里斯水迷宫试验检测吴茱萸碱及其衍生物对改善APP/PS1小鼠学习和记忆的作用。
在本研究中，合成了一系列氧代和硫代吴茱萸碱衍生物。几种衍生物显示出比吴茱萸碱更低的细胞毒性和更强的神经保护作用，并引起增强的认知改善，特别是在APP/PS1小鼠的空间记忆测试中。
我们的研究为开发用于AD化学干预和治疗的新型吴茱萸碱衍生物提供了思路。
