基于药物代谢组学及系统药理学技术研究刺五加叶治疗缺血性脑中风的药效物质基础及作用机制

Ischemic stroke, a common cerebrovascular disease, is of increasing seriousness because of the high incidence and deformity as well as lack of effective treatment and prognosis drugs. In recent years, although Chinese traditional medicine shows the unique advantages in the treatment of the ischemic stroke, its pharmacodynamic material basis and function mechanism are still not very clear. In order to solve the existing problems, we propose to study the pharmacodynamic material basis and function mechanism of leaves of Acanthopanax Senticosus Harms for treating ischemic stroke based on pharmaco-metabonomics and systems pharmacology. Firstly, we prepare different fractions from the leaves of Acanthopanax Senticosus Harms and screen effective fractions using the in vitro activity evaluation method. Secondly, the pharmaco-metabonomics and systems pharmacology study will be carried out to clarify the multi-target function mechanism of the leaves of Acanthopanax Senticosus Harms for treating ischemic stroke. Moreover, the pharmacodynamic material basis of the leaves of Acanthopanax Senticosus Harms will also be clarified through the in vivo absorption and metabolism research combined with pharmacokinetics study. According to the above-mentioned results, the pharmacodynamic material basis and multi-component, multi-target function mechanism of leaves of Acanthopanax Senticosus Harms in treating ischemic stroke and its complications will be clarified. This research will benefit the clinical application and promote the research of innovative drugs from leaves of Acanthopanax Senticosus Harms.

缺血性脑中风是一种严重威胁人类健康和生活质量的脑血管疾病，却缺少有效的治疗和预后药物。近年来，中药在该病治疗中显示出了独特的优势，但是多存在药效基础不清和作用机制不明问题。针对目前存在的问题，本项目基于中医药理论的整体观、动态观和辩证观，以刺五加叶为研究对象，以慢性缺血性脑中风大鼠为研究模型，从药物对整个疾病网络的协同调节作用出发，基于系统生物学的研究思路，首先通过柱色谱技术结合体外活性评价方法筛选得到刺五加叶活性组分；其次，通过代谢组学和系统药理学方法研究活性组分对疾病主要通路及关键病理网络的影响，阐明其整体作用机制，与此同时进行活性组分体内外吸收代谢研究及药代动力学研究，阐明其药效物质基础。本项目将解决刺五加叶治疗缺血性脑中风的药效物质不明确、作用机制不清楚的关键科学问题，为刺五加叶的临床应用及相关创新药物的研发提供科学依据。

本项目以慢性缺血性脑中风大鼠为研究模型，从药物对整个疾病网络的协同调节作用出发，基于系统生物学的研究思路研究刺五加叶治疗缺血性脑中风的药效物质基础和作用机制。首先利用DM130大孔树脂分离制备得到刺五加叶总提液、水洗部位、40%乙醇洗脱部位、70%乙醇洗脱部位和90%乙醇洗脱部位，并利用体外抗氧化和PC12神经细胞损伤保护作用模型对各部位活性进行评价，筛选得到综合活性最好的部位为40%乙醇洗脱部位；其次，通过代谢组学研究发现刺五加叶活性部位主要通过调节牛磺酸和次牛磺酸、花生四烯酸、半胱氨酸和蛋氨酸、类固醇激素生物合成、色氨酸、酪氨酸和嘧啶代谢途径发挥作用；网络药理学研究表明刺五加叶活性部位主要从改善免疫应答与抑制炎性反应、调节神经递质紊乱与改善神经递质的活性、抑制兴奋性毒性与减轻氧化应激损伤、改善内皮功能障碍、改善脑部血液循环与保护血脑屏障和促进凝血与抑制血栓形成等方面发挥作用。最后，通过PK-PD关联分析，进一步证实金丝桃苷、槲皮苷、槲皮素、1,3-二咖啡酰奎宁酸、4,5-二咖啡酰奎宁酸和咖啡酸 6 种化学成分在大鼠体内的动力学过程与内源性神经递质的含量变化呈相关性，是刺五加叶治疗缺血性脑中风的重要物质基础。本项目不仅系统阐释了刺五加叶治疗缺血性脑中风的药效物质和作用机制，为刺五加叶的临床应用及相关创新药物的研发提供科学依据，并且可以为中药药效物质基础及作用机制研究提供方法学借鉴。发表论文16篇，其中SCI论文12篇，中文核心论文3篇，会议论文1篇。获得吉林省科技进步一等奖1项，培养硕士研究生3名，博士研究生2名，博士后1名。