基于谱效关系的苗药赶黄草抗脑缺血/再灌注损伤药效物质基础及其机制研究

Ischemic cerebrovascular disease is one of main diseases causing disability and death, searching for new drugs against cerebral ischemia with less side effects is always a hot issue in the world. Recently, we found that a Miao medicine, Penthorum chinense Pursh, had significant activity against CIRI by using middle cerebral artery occlusion model in mice, which indicated the possibility of developing cerebrovascular protective agent from P. chinense. This project will conduct spectrum-activity correlation analysis of chemical information of fingerprints and pharmacodynamic index information through a variety of mathematical models, and speculates the contribution of each chromatographic peak. Then the potential effective constituents will be isolated and identified. Since inflammatory response and oxidative stress are two important pathological mechanisms of CIRI, the action mechanisms based on JNK and Nrf2 pathways will be performed. Accomplishing these objectives will provide the theoretical evidences for P. chinense to treat cerebral ischemia, and extend its clinical uses, and also provide the beneficial references for the further study of other Ethnomedicine with definite therapeutic effects.

缺血性脑血管病是引起人类致残、死亡的最主要疾病之一，寻找疗效好、副作用少的防治缺血性脑血管病的理想药物一直是研究的热点。申请人前期利用小鼠大脑中动脉栓塞模型发现苗药赶黄草具有显著的抗脑缺血/再灌注损伤（cerebral ischemia reperfusion injury，CIRI）的作用，具有开发成脑血管保护药物的前景。本项目以赶黄草为研究对象，通过建立多种数学模型，对指纹图谱化学信息与药效指标信息进行谱效关联分析，推测各色谱峰的药效贡献，明确潜在药效成分，并通过潜在药效成分的分离、鉴定及活性确证，阐明药效物质；再从CIRI的重要病理机制炎症反应和氧化应激入手，基于JNK和Nrf2通路，进行多途径、多靶点抗CIRI机制研究。建立“药效成分发现--靶向分离--活性确证--作用机制研究”多学科交叉的研究模式，为扩大赶黄草适应症提供理论依据，也将为疗效确切的民族药的深入研究提供有益的借鉴。

寻找疗效好、副作用少的防治CIRI的理想药物一直是医药界关注的热点。本项目首次发现苗药赶黄草具有抗CIRI的作用。首先利用谱效关联分析发现了抗CIRI潜在药效成分；再通过潜在药效成分的分离、鉴定与药效确证，揭示了赶黄草抗CIRI药效物质主要为黄酮和有机酸类。共分离鉴定药效相关化合物40个。机制研究结果显示赶黄草可能通过抑制炎症反应和氧化应激损伤两种途径，基于MAPK和Nrf2通路发挥抗CIRI作用。特别重要的是：赶黄草对MCAO大鼠的神经保护作用与阳性药相当。以上结果提示，赶黄草具有开发成抗CIRI的重要价值，值得进行深入的研究。本项目的研究成果已申请并受理一项国家发明专利，为开发具有自主知识产权的民族药创新药物奠定重要基础，该成果具有转化的价值。本项目的系列研究成果将为赶黄草的深入开发提供新的思路和启示，助力赶黄草苗药大品种发展之路。另外，本项目关于赶黄草抗CIRI药效物质基础的相关研究成果为更为科学的制定赶黄草的质量标准提供了重要的依据。