基于代谢组学及代谢相关性的天麻酚类成分治疗血管性痴呆作用机制研究

Vascular dementia (VD) is a common, frequently-occurring disease of aging society, which is a serious threat to the patient's quality of life and health, and also causes a heavy burden to the society, so VD's control is of great urgency. Gastrodia elata is commonly used for the treatment of cardiovascular and cerebrovascular diseases, which presents good curative effect for alzheimer's and parkinson's disease. But the study of gastrodia elata in the treatment of VD is still confined to crude extract or known active ingredients, such as gastrodin, p-hydroxybenzyl alcohol, etc., and the mechanism of action is not fully and deeply understood. This research selected parishins and hydroxylbenzyl nucleosides as breakthrough point to evaluate efficacy of phenolic constituents of gastrodia elata from the perspective of regulation of endogenous metabolites and metabolic pathways by screening biomarkers of VD, and tracing metabolic pathway and target proteins using metabonomics. In combination with traditional pharmacodynamic method and variance analysis between biomarker and endogenous metabolites, the interfering action of phenolic components of gastrodia elata to metabolic pathways of VD animals and mechanism of action were revealed. This research provides an in-depth understanding of material basis and acting mechanism of gastrodia elata in the treatment of VD and promotes the development of innovative traditional Chinese medicine for VD.

血管性痴呆（VD）为老龄社会的常见病、多发病，严重威胁患者的生活质量和生命健康，也给社会造成了沉重的负担，因此对于VD的防治刻不容缓。天麻为治疗心脑血管疾病的常用中药，对老年痴呆、帕金森病等具有较好的疗效。但是目前对于天麻治疗VD的研究主要集中在天麻粗提物或已知活性成分天麻素、对羟基苯甲醇等，且对其作用机制的认识不够充分和深入。本课题选择天麻特征酚类成分parishin类和羟苄核苷类为研究切入点，采用代谢组学方法筛选血管性痴呆的代谢标志物，追溯其代谢通路及靶向蛋白，从调控内源性代谢物及代谢途径的角度，评价天麻酚类成分的有效性，并与传统药效学的评价方法对接验证，同时结合代谢标志物与外源性代谢物的相关性分析，明确天麻酚类成分对VD动物代谢途径的干预作用，阐明其作用过程，揭示作用机制。课题的实施对天麻治疗VD的物质基础及作用机理有了更深入的认识，对治疗VD的创新中药研发具有推动作用。

天麻为治疗心脑血管疾病的常用中药，对老年痴呆、帕金森病等具有较好的疗效。但是目前对于天麻研究主要集中在天麻粗提物或已知活性成分天麻素、对羟基苯甲醇等，且对其作用机制的认识不够充分和深入。本项目通过制备天麻提取物，精制组分，单体成分及其配伍组分，采用东莨菪碱所致小鼠痴呆模型，结合动物行为学，Aβ及H2O2诱导的SH-SY5Y损伤细胞模型，试剂盒检测等方法研究天麻及其相关成分的疗效，筛选天麻活性成分。同时采用代谢组学结合蛋白质组学方法筛选痴呆的特异性标志物，构建代谢通路，从而阐明痴呆发病作用机制。结果显示天麻酚类成分和核苷类成分存在明显的神经保护作用，且这两类精制组分在1：10的配比下疗效最佳，对于单体化合物以天麻苷元，巴利森苷E，羟苄腺苷及其代谢产物的活性最为突出，同时根据多组学研究结果显示亚油酸代谢通路与痴呆发病作用显著相关，为进一步探讨痴呆作用机制及新药研发提供强有力的支撑。根据上述的结果进一步研发了全新的天麻质量控制策略，包括指纹图谱法，总天麻素和天麻苷元质控法及总天麻苷元质控法，并与现有药典方法及多成分质控法进行了比较，实验结果可用于指导药典关于天麻质量控制方法的进一步完善。课题的实施对天麻治疗痴呆的药效物质基础及作用机理有了更深入的认识，对治疗心脑血管疾病的创新中药研发具有推动作用。