荭草素-2-o-β-d-半乳糖苷抑制小胶质细胞炎症反应及其机制研究-study on the inhibitory effect of orientin - 2 - o - β - d - galactoside on microglia inflammatory response and its mechanism.docx

目录目录···························································································3前言···························································································1材料与方法·······················································································3实验材料·····················································································3实验方法·····················································································4结果··························································································12讨论··························································································24结论··························································································27参考文献·························································································28综述····························································································33缩写词表·························································································43致谢··························································································44前言神经退行性疾病(Neurodegenerativedisease)是一类以大脑和脊髓的神经元细胞丧失为特征的疾病，如阿尔茨海默病（Alzheimerdisease，AD），帕金森病（Parkinson’sdisease，PD），多发性硬化症（MultipleSclerosis，MS）等。目前对于神经退行性疾病的病因和发病机制尚未完全研究清楚，遗传因素，环境因素，氧化应激反应，线粒体功能障碍等假说被认为与其发病有着密切的联系。越来越多的研究表明神经炎症参与神经退行性疾病的发生和发展过程[1]。McGeer等报道在PD病人脑内黑质纹状体中存有大量激活的小胶质细胞，并且相关炎症因子如肿瘤坏死因子-α（TNF-α），白介素-1β（IL-1β）等均有高表达[2,3]。在AD患者脑内老年斑周围也发现大量激活的小胶质细胞聚集[4]。在MPTP诱导的PD动物模型中，小胶质细胞的激活被证明发生在多巴胺能神经元病变早期[5]。以上研究结果表明，神经炎症尤其是小胶质细胞介导的神经炎症，在神经退行性疾病的发生和发展过程中有着重要的作用。在中枢神经系统中，小胶质细胞被认为是最主要的免疫监视和免疫效应细胞，其大约占脑内胶质细胞总数的5%-20%[6]。从形态上区分，小胶质细胞可分为两类：分枝状和阿米巴样。不同的形态有着不同的功能，在正常生理状态下小胶质细胞处于静息状态，呈分支状，监视着脑内微环境的变化。当中枢神经系统受到如炎症，损伤等刺激因素刺激时，处于静息状态下的小胶质细胞迅速从分支状转变为阿米巴样，即小胶质细胞的激活。激活的小胶质细胞向病灶部位迁移，起到抗原提呈和吞噬病原体的作用[7-9]。研究表明，激活的小胶质细胞能够释放大量炎症介质，如一氧化氮（NO），TNF-α，IL-1β，前列腺素E2（PGE2）等。这些炎症介质能够损伤神经元，危害大脑功能[10]。例如在生理状态下NO和PGE2生成过程的关键酶iNOS和COX-2在小胶质细胞中处于低表达状态，当小胶质细胞激活后，iNOS和COX-2表达升高，进而产生大量NO和PGE2，从而导致神经