一叶萩型生物碱类成分抑制神经炎症的作用机制和构效关系研究

神经胶质细胞过度活化导致的神经炎症反应是加剧阿尔茨海默症(AD)患者神经元凋亡和突触功能异常的重要原因之一。神经炎症抑制剂可通过抑制小胶质细胞中炎症细胞因子的释放，特异性地降低神经元损伤和突触功能异常，已成为抗AD药物研发的一个重要方向。我们前期从一叶萩总碱部位分离鉴定了一系列结构多样的生物碱(包括3类新骨架化合物)，其中部分A环取代的新型一叶萩型生物碱对LPS诱导的小胶质细胞显示出良好的神经炎症抑制活性，且毒性较低。初步的体内实验结果显示，一叶萩总碱可显著改善AD小鼠的学习记忆及认知功能障碍，并降低大脑皮层区小胶质细胞的过度激活。本项目拟在前期工作基础上，对一叶萩中A环取代的新型一叶萩型生物碱类成分进行针对性分离，结合结构修饰手段构建该类型化合物样品库，并对其抑制神经炎症的活性进行评价及开展构效关系和作用机制研究，为研究和开发高效、低毒的神经炎症抑制剂类抗AD药物提供科学依据。

Neuroinflammation caused by microglial over-activation plays a significant role in Alzheimer's disease (AD). Neuroinflammation inhibitors could reduce the neuronal apoptosis and synapse dysfunction via the suppression on secretion of proinflammatory cytokines. Thus, targeting neuroinflammation has become an important therapeutic intervening strategy for treating AD. Our previous phytochemical study on the roots of Fluggea suffruticosa had led to the isolation of a series of Securinega alkaloids with diverse structures, including three new classes of Securinega alkaloids with unprecedented skeletons. Preliminary study had shown that some A ring modified Securinega alkaloids possessed significant neuroinflammation inhibition effects on LPS-induced BV2 cells. Besides, we found that the total alkaloids extracts could significantly improve the learning and memory deficits of AD model mice, and effectively suppress the over-activation of microglia in the cortex. Based on our previous study, we are planning to carry out further phytochemical and structure modification studies on the novel A ring modified Securinega alkaloids from Flueggea suffruticosa, and establishing a compound library of A ring modified Securinega alkaloids with diverse structures and various stereochemistry. Furthermore, the inhibition abilities of those alkaloids on neuroinflammation, as well as their structure-activity relationship (SAR) and action mechanism will also be studied. Our findings could be used as scientific evidence and foundations for the new drug development for the treatment of AD.