维药琐琐葡萄防治阿尔茨海默病的机制研究

Alzheimer's disease (AD) is a kind of degenerative disease with a high incidence in the elderly. The main symptoms of the patients are progressive memory loss and cognitive dysfunction, which seriously do harm to human health and life. With the aging of society ,the incidence of AD showed a rising trend in recent years. As the etiopathogenisis and pathological mechanisms of AD are very complex, so that there is still lack of effective treatments at present. In recent years,the effects of Traditional Chinese Medicine(TCM) in AD therapy received a increasing attention. The natural medicine has wide variety of sources, stable and easy to use, it is worth further research,development and utilization. Uighur medicine as an important part of Chinese traditional medicine,constantly absorbing advanced scientific technology in order to carry out the basic theory of the Uygur medicine and drug discovery research. The extracts of Uighur Medicine SuoSuo grape, have important Biological functions,such as antioxidant, anti-mutagenic,enhance immunefunction and anti-aging ,et al. This project study protective effects and mechanisms of extracts of Uighur Medicine SuoSuo grape on AD in vivo and in vitro, through establish cellular model and animal models of AD,applicated Flow cytometry ,RT-PCR, Western blot, immune biochemical and other methods to explore the neuroprotective effect and mechanism of the extracts of Uighur Medicine SuoSuo grape, such as cell apoptosis, signal transduction pathways, relase of neurotransmitter, dementia-related gene expression ,et al.The objective of our experiment is to study the neuroprotective effects of extracts of Uighur Medicine SuoSuo grape with a view to preventing and healing neurodegenerative disorders such as Alzheimer's disease and advancing Uighur medicine research, development and utilization.This research can provide reference information for the development of new anti-dementia drugs. Meanwhile, it also aims to bring into a new method for exploitation and utilization of abundant grape resource in Xinjiang to produce some new effective and cheap drugs and promote the development of region's economy and society.

阿尔茨海默病（AD）是一种老年性神经退行性疾病，发病机制较为复杂，尚无有效的疗法，是老龄化社会面临的重大问题。维吾尔医学是祖国传统医学宝库的重要组成部分，对老年性疾病的预防和治疗独具特色和方药治疗方法。前期研究发现，维药琐琐葡萄总黄酮、总多糖等有效成分具有抗氧化、抗衰老和调节免疫等功效。故本研究拟从β淀粉样蛋白（Aβ）神经毒性出发，利用琐琐葡萄提取物及其活性组分，通过模拟AD细胞模型、动物模型的药物干预，以及AD相关细胞和分子指标的鉴定，研究琐琐葡萄提取物的神经保护及治疗作用，筛选出抗老年性痴呆活性成分，明确该药作用的机制及分子靶点，为基于琐琐葡萄活性组分的新药研发及维医药物质基础研究提供科学依据。

阿尔茨海默病亦称老年性痴呆（AD），以慢性进行性不可逆记忆减退、认知障碍和人格改变为主要临床特征。随着社会的老龄化，其发病率呈逐年上升趋势。课题组前期研究显示维药琐琐葡萄中提取的总黄酮（VTF）、总多糖（VTP）具有抗氧化、抗衰老作用，本课题通过对大鼠双侧海马注射Aβ25-35制备阿尔茨海默病（AD）大鼠模型， Aβ25-35诱导PC12细胞建立细胞模型，运用免疫组织化学、RT-PCR、Western blot、电镜、流式细胞等实验技术，探讨VTF、VTP对AD模型的神经保护作用及机制。通过行为学、细胞形态、超微结构的比较， VTF、VTP在一定剂量时可以有效的改善AD大鼠学习记忆能力并且减轻神经细胞损伤。VTF、VTP通过保护大鼠氧化还原系统，改善AD大鼠神经元的氧化损伤；VTF、VTP降低大鼠脑组织和血清中 AchE的含量，提高ChAT活力，从而改善中枢胆碱能损害；VTF、VTP通过下调BACE -1表达抑制APP代谢，减少神经毒性物质Aβ1-42的生成；VTF、VTP能增强BDNF和Syt-1的活性，对突触可塑性有促进作用；VTF、VTP通过抑制NF-κBp65的活性从而抑制下游炎症因子TNF-α、IL-6、IL-1β的生成，其机制是抑制IκB-α磷酸化，调节NF-κB/IкB-α信号通路的作用，控制免疫炎症级联反应保护大脑神经细胞。VTF、VTP干预AD细胞模型后，细胞受损程度减轻，细胞存活率明显增加，其作用是通过调节APP代谢途径，减轻Aβ毒性损伤；Aβ25-35诱导细胞凋亡可能是通过抑制p-Akt的活性并调节凋亡相关基因表达，VTF、VTP对PI3K/Akt信号通路相关蛋白Akt磷酸化有促进作用，下调Caspase-3、上调Bcl-2的蛋白表达，从而抑制细胞凋亡。本研究通过动物行为学、细胞形态和超微结构、基因和蛋白表达的分析，表明VTF、VTP是通过抗炎症反应、抗氧化、抗凋亡、抗突触损伤、调节神经递质释放以及APP代谢等作用机制，减轻Aβ神经毒性作用引起的神经细胞损伤，缓解阿尔茨海默病实验动物和细胞模型的病理损害，具有神经保护用，研究结果为寻找防治AD药物以及探索VTF、VTP作用靶点提供了实验依据。