补气、活血、解毒三种方剂抗脑缺血的代谢组学研究

Cerebral ischemia is a common disease, which has acute developing and high disability rate. As pathophysiology of cerebral ischemia is complex and involves many factors during the developing of the disease, the cerebral ischemia has always been the study focus. In this project, metabolomics of cerebral ischemia will be studied. Amino acids, neurotransmitter, lactic acid and other small molecule metabolites, which are related with cerebral ischemia, were chosen as analytical targets. Cerebral microdialysis will be applied to collect the perfusates from the specific brain region continuously. Through qualitatively analysis of target metabolites in blood and perfusates, the biomarkers related with developing of cerebral ischemia will be found.. Based on the above study, metabolomics targets and action mechanisms of three typical Chinese medicinal formulas to treat cerebral ischemia were studied and compared. The three typical Chinese medicinal formulas are Huangqi injection, Danhong injection and Qingkailing injection. In Chinese medicinal theories, the three formulas have different characters, which are “invigorating Qi”, “activating Blood” and “detoxifying” respectively. By this study, the Chinese medicinal theories about the three injections would be explained...

脑缺血是我国的常见病、多发病，具有发病急、发展快、致残率高的特点。脑缺血的病理生理机制复杂，在疾病的发展过程中涉及多种环节，因此一直是医药学研究的重点。本研究以脑缺血相关的多种内源性小分子代谢物（如：氨基酸类、单胺及其它神经递质、乳酸、葡萄糖、胆固醇等）为分析靶标，采用代谢组学的研究方法，结合微透析取样技术, 对脑缺血急性期不同时间点下的血浆及脑组织透析液中的代谢物整体上进行定量、动态分析，通过模式识别探索发现脑缺血相关的生物标志物及其变化规律。. 在此基础上，选取临床疗效确切的3种代表方剂为探针药物，分别从补气（黄芪注射液）、活血（丹红注射液）、解毒（清开灵注射液）三个角度对脑缺血进行干预，通过3种方剂抗脑缺血的代谢组学研究，整体上对三种注射剂的治疗特点进行评价，确定各自的代谢靶标和作用机制，从而指导临床用药，揭示“补气”、“活血”、“解毒”3种中医治法的科学内涵。

本研究首先建立了脑缺血代谢标志物数据库并进行了生物信息学分析研究，为进一步的实验研究涉及的代谢靶标的选择、标志物的鉴定、代谢通路的验证等方面提供参考。. 基于以上研究结果，在实验实施阶段选择了与脑缺血病理过程直接相关的氨基酸类神经递质为分析目标，采用靶向代谢组学研究策略，建立了大鼠血浆中氨基酸类神经递质的分析方法，对正常与脑缺血病理状态下的生物样本进行动态分析，通过模式识别确定脑缺血的生物标志物及其变化特征，对黄芪注射液、丹红注射液、清开灵注射液3 种方剂抗脑缺血的作用机制进行研究，确定了3种方剂的氨基酸代谢调节标志物，从而阐释 “补气”、“活血”、“解毒”3 种中医治法的科学内涵。. 此外，为了深入研究药物脑保护机制，针对极性脂质（PCs、SMs、Cers）建立了细胞代谢组学分析方法，从细胞水平，采用小鼠原代神经元糖氧剥夺模型，OGD模型，进一步对OGD模型所导致的神经元损伤的病理机制及丹红注射液、黄芪注射液、清开灵注射液的脑保护作用进行研究。目前已完成对OGD所导致的神经元损伤模型的评价以及丹红注射液的作用机制的评价。