以抑制小胶质细胞活化为靶标探索龙血竭抗阿尔茨海默病的物质基础及作用机制

项目名称： 以抑制小胶质细胞活化为靶标探索龙血竭抗阿尔茨海默病的物质基础及作用机制

项目编号： No.81473330

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 侯悦

作者单位： 东北大学

项目金额： 71万元

中文摘要： 小胶质细胞活化诱发的神经炎症是阿尔茨海默病（Alzheimer's disease，AD）产生和发展的重要原因，已成为抗AD药物研究的新靶标。我们新近研究首次发现名贵中药龙血竭能够显著抑制小胶质细胞活化。进一步活性导向的分离和动物实验确证了其活性成分之一LXJ05的抗AD作用及体内小胶质细胞活化的抑制作用。由此，本项目拟继续阐明龙血竭活性部位的物质基础；使用细胞水平的筛选模型评价其小胶质细胞活化的抑制活性并利用整体动物模型进行在体活性确证；综合运用分子生物学方法，以ROS/MAPKs/NF-κB通路为切入点，利用小胶质细胞系及APP/PS1转基因小鼠，阐明其活性成分如何通过对此信号通路的调控抑制小胶质细胞活化释放炎性介质、从而发挥对神经元的保护作用机制，明确其体内外分子信号调控机制的相关性，以期为揭示传统中药龙血竭抗AD这一全新的药理活性及物质基础奠定实验基础，为中药现代化提供实验依据。

中文关键词： 龙血竭；小胶质细胞；阿尔茨海默病；物质基础；作用机制

英文摘要： Microglia activation-induced neuroinflammation is beliveved to play a critical role in the pathology of Alzheimer's disease (AD). Therefore, it is of important significance to find safe and effective inhibitors of microglia activation. In our previous study, we have found for the first time that Chinese Dragon's Blood can sigificantly inhibit microglia activation. Further study has confirmed its effect against AD tested by using AD animal model.It has also been revealed that its inhibitory effect of microglia activation may be associated with the inhibition of ROS/MAPKs/NF-κB pathway. Based on our previous work, further investigation will be done in this project including: 1) isolation and identification of chemical compounds from Chinese Dragon's Blood by using LC-MS analysis method. 2) evaluation of the inhibitory activity of active compounds on microglia activation and further confirmation of the in vivo activity of the active compounds by using the AD animal model. 3) elucidation of mechanism and targets of the active compounds involved in the inhibitory activity on microglia activation by using both microglial cell line and APP/PS1 transgenic mice, clarification whether ROS/MAPKs/NF-κB pathway is involved in the activity of Chinese Dragon's Blood in its inhibitory effect on microglia activation and neuronal protective effect. 4) clarification of the material basis and mechanism of Chinese Dragon's Blood against AD via inhibiton of activated microglia. The purpose of this project is to provide scientific supports for the discovery of novel pharmacological activity of the traditional Chinese medicine Dragon's Blood and related material basis, as well as to establish the experimental foundation of the discovery of new drug for the treatment of AD.

英文关键词： Chinese Dragon's Blood;Microglia;Alzheimer's disease;Material basis;Mechanism