代谢处置与机体响应双导向的银杏内酯治疗缺血性脑卒中作用机制研究

Cerebral ischemic stroke is one of the major neurological disorders and severely detrimental to public health. Currently, therapeutic-pharmacological agents for acute stroke remains to be a significant unmet need in clinic. Ginkgolide is major constituents of Ginkgo biloba.L that exerts neuroprotective effects. However, the relationship bewteen in vivo disposition of ginkgolide and its apparent efficacy is still uncertain. The therapeutic machanism of ginkgolide need to be further investigated. This project integrate the core ideas and analytical techniques of pharmacokinetics, pharmacodynamics and metabonomics, propose a novel research mode based on therapeutic efficacy and under the guidence of drug metabolic disposition (drug distribute in organs) and body reponses (endogenous metabolites changes). After ensure hosiltic pharmacological effects, we will confirm the in vivo components and traget tissues of ginkgolide by comparision of matabolism and disposition in physiological and pathological condition, and select appropriate in vitro cellular models for machanism investigation. Target and nontarget metabonomics analytical techniques will be applied to discover the biomarkers of ischemic stroke and ginkgolide action, and characterize dynamic profile of endogenous metabolites. Based on bioinformatics platform, an “Ischemic stroke-Ginkgolide intervention ” metabolic network will be established to predict protential targets of ginkgolide. The influence of ginkgolide to key genes and enzyme in metabolic pathway will be verified in molecular level. This study provide scientific basis to reveal therapeutic machanism of ginkgolide on ischemic stroke and a feasible paradigm for other natural medicines research.

缺血性脑卒中是危害人类生命健康的主要疾病之一，目前临床上仍缺乏有效的治疗药物。银杏内酯是中药银杏发挥脑保护作用的关键成分，但其体内过程与表观药效间的关联不明确，治疗作用机制亟待深入研究。本项目整合药代动力学-药效动力学-代谢组学的思路与方法，创新性提出以整体药效为核心，以代谢处置（药物在体内分布）和机体响应（内源性代谢物变化）为双重导向的研究模式，在明确整体药效的前提下，比较生理/病理状态下银杏内酯在体内的代谢分布规律，确定其体内成分和药效作用靶组织，据此建立体外药效评价模型；综合应用非靶向/靶向代谢组学分析技术，发现与疾病/药物干预相关的生物标志物群并描述机体内源性代谢物谱的动态变化特征；利用生物信息平台构建“脑梗塞-银杏内酯干预”代谢网络，推测药物作用靶标群，并在分子水平验证银杏内酯对相关代谢通路基因和酶的作用。以期阐明银杏内酯对脑缺血保护作用的可能机制，为中药活性成分的研究提供借鉴。

缺血性脑卒中是危害人类生命健康的主要疾病之一，目前临床上仍缺乏有效的治疗药物。银杏内酯是中药银杏发挥脑保护作用的关键成分，本项目整合药代动力学-药效学-代谢组学的研究思路与方法。对银杏内酯类主要成分的代谢处置规律及治疗缺血性脑卒中的代谢调节作用机制开展研究。研究证实银杏内酯在动物模型水平能够减小脑缺血造成梗死面积，缓解神经行为学损伤，提高抗氧化应激能力；揭示了银杏内酯类成分在生物体内的动态变化规律，阐明银杏内酯类化合物的血浆经时过程；主要经过肝脏代谢后，通过肠道和肾脏排出；且发生药物相互作用的可能性很小。结合代谢组学研究发现，银杏内酯在疾病状态下脑部暴露量显著提高，能够通过调节缺血再灌注造成的糖酵解，TCA循环，磷酸戊糖通路，氨基酸代谢异常，改善能量代谢衰竭，提高内源性抗氧化能力而发挥神经保护作用。基于银杏内酯对内源性代谢调节作用特点开展缺血预适应代谢调节作用研究，发现预适应能够通过对葡萄糖代谢的适应性调节缓解脑缺血再灌注损伤。本项目研究结果揭示了银杏内酯类成分的代谢处置特征及代谢调节作用,为其临床应用及新药开发提供科学依据。