从内质网应激途径的细胞保护角度探讨栀子抗帕金森病的活性成分及作用机制

项目名称： 从内质网应激途径的细胞保护角度探讨栀子抗帕金森病的活性成分及作用机制

项目编号： No.81503412

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张扬

作者单位： 吉林大学

项目金额： 18万元

中文摘要： 内质网应激（ERS）介导的细胞凋亡参与帕金森病（PD）的发病过程。有报道栀子主要药效成分环烯醚萜类化合物可抑制ERS相关蛋白表达，降低凋亡相关蛋白裂解，有助于神经退行性疾病病变的改善。课题组经临床疗效评价及离体整体实验证实，黄连解毒汤及其组成生药栀子具有调节多巴胺代谢和神经保护作用。由此推测，栀子可能通过干预ERS的自身保护以及过度应激诱发的凋亡机制，发挥其神经保护作用，从而达到防治PD的目的。前期工作将计算机虚拟筛选与体外生物活性评价结合，初步筛选出可抑制MPP+诱导SH-SY5Y细胞凋亡的栀子活性化合物。本项目将以此为突破口，以ERS标志物为靶点，依托计算机虚拟筛选技术，结合药物筛选PD细胞模型和动物模型，以期确定栀子中抑制DA能神经元凋亡的活性成分；进而阐明其针对ERS生存和凋亡途径的细胞保护机制，为进一步开发抗PD的药物提供科学依据和研究思路。

中文关键词： 活性成分；帕金森病；内质网应激；细胞凋亡；分子对接分析

英文摘要： It has been reported that endoplasmic reticulum (ER) stress-induced apoptosis is involved in the pathology of PD. Recent studies show that iridoids, one of the major active constitutents in Gardenia jasminoides Ellis, reduced the expression of ER stress-associated protein and the cleavage of apoptosis-associated protein. Thus, the agent may be effective for treating neurodegenerative diseases including PD. We have confirmed that Huanglian jiedu decoction (HJD), a traditional Chinese medicine compound recipe, and Gardenia jasminoides Ellis could regulate dopamine (DA) metabolism and possess the neuroprotective effects on neuronal injury according to clinical trials , cell research and animal experiments. Therefore, we hypothesized that Gardenia jasminoides Ellis protects neurons from ER stress response-signaling pathway and may be valuable in treating PD. In our preliminary screening, we identified some of active constitutents that could inhibit MPP+-induced apoptosis in SH-SY5Y cells by the means of combined computer-virtual screening and in vitro biological activity evaluation. In this study, first, we predicted the compounds of Gardenia jasminoides Ellis based on computer-virtual screening and then evaluated the neuroprotective effect of active constitutents against ER stress-induced apoptosis in cell culture and animal models of PD. Finally, we investigated the cytoprotection mechanism via ER stress-induced survival and apoptosis. The study aims to provide scientific evidence and ideas for the development of drugs against PD.

英文关键词： Active Constitutents;Parkinson`s Disease;Endoplasmic Reticulum Stress;Apoptosis;Molecular Docking Analysis