基于成分与归经关联的“活性化学成分群模拟炮制”探究川芎酒制治疗脑血栓的科学内涵

In recent years, investigation on traditional Chinese medicine (TCM) has risen to national strategic height. However, the employment of prepared Chinese crude drug is still quite confused and such issue has not been solved well, which largely affects its curative effects in clinic. As a traditional and vital Chinese medicine preparation technology, it is very meaningful to investigate on Chinese medicine processing mechanism. Although a large number of researches have attempted to reveal the mechanisms of Chinese medicine processing, most reports are still limited in changes of chemical compounds before and after processing or combined with pharmacological activities to find out marker components. This practice is similar to the pattern of investigation on western drugs, which can partly expound marker components with the quantitative and qualitative changes, but neglects the impact of processing to drug properties, especially to meridian distribution. Based on this, we innovatively put forward a promising methodology of combination between marker components and meridian distribution on representative drug Chuanxiong Rhizoma and systematically investigate on the changes of chemical constituents, efficacies, and their correlation, so as to find potential real marker components. Furthermore, we propose a novel concept of ‘simulation of Chinese medicine processing on marker components’ and for the first time, preparation and characterization of carbon nanohorn-quantum dot nanocomplex have been employed to pack marker components, which can imitate its potential ways of meridian distribution. We hope that our established novel TCM delivery system can reasonably explain processing mechanisms, dig out a better precision drug, and promote the modernization of TCM.

近年来，中医药研究已上升到国家战略高度，但中药饮片市场混乱的问题一直未能得到解决，严重影响其疗效。炮制作为制备中药饮片的关键制药技术，对其机理的探讨意义重大。虽然对中药炮制机理已有很多报道，但大部分的研究仍只停留在关注炮制前后化学成分的变化或与药理活性结合找出差异性成分的角度来阐释炮制机理。虽然这种借鉴西药的研究模式挖掘出了中药炮制以后“质和量”变化的活性化学成分，但却忽视了炮制对药性的影响，尤其是炮制对归经的作用。鉴于此，本项目立足于活性成分与归经关联的角度，以代表性药物川芎为例，通过系统的化学成分与药效相关性研究，找出其潜在的活性化学成分群，并采用“活性化学成分群模拟炮制”的新视角，创新性的将单壁碳纳米角与量子点组成的纳米复合材料包裹川芎饮片中的活性化学成分群用于模拟其潜在的归经形式。希望构建的这种中药新的递药系统能更加合理地解释中药炮制机理，挖掘更好的精细化新药，推动中药现代化进程。

本课题立足于活血化瘀药川芎酒炙增效与酒炙升提的物质基础与机理研究，首先从体内外化学成分质和量的变化入手，系统进行了川芎酒炙前后HPLC指纹图谱变化规律研究，挥发性成分、非挥发性成分变化规律研究，在正常大鼠和模型大鼠体内的药代动力学特征比较研究，组织分布研究，对于脑缺血再灌注模型大鼠的药效及谱效相关性分析等研究。通过炮制过程中指纹图谱的动态变化规律从客观上规范炮制工艺为黄酒润透后文火炒制20 min。通过GC-MS法进行炮制过程中挥发性成分的变化规律研究共鉴别挥发性成分44种，同时炮制过程会造成程序升温时温度低于135 ℃的挥发性成分的散失，对大于135 ℃出峰的挥发性成分含量影响不大。通过UHPLC Q Exactive focus Mass的方法进行酒炙前后非挥发性成分变化规律研究共鉴别成分145种，同时发现因酒炙的原因会造成糖类、氨基酸类成分含量升高，同时引入川芎中没有的成分-洛伐他丁，此外酒炙过程中美拉德反应的产物含量也增高。通过川芎酒炙前后主要药效成分在正常和模型大鼠体内的药代动力学过程比较研究发现，生川芎与酒川芎在正常和模型大鼠体内的药代动力学特征有明显差异，相比正常大鼠，酒川芎在在模型大鼠体内多种成分有较高的Cmax以及AUC，可更好的体现酒炙增效。通过酒炙前后组织分布比较研究发现酒炙之后藁本内酯和洋川芎内酯A在脑中的分布增加，此可能为“酒炙升提”的内在原因，同时发现酒川芎和生川芎的阿魏酸在肠道中的代谢产物含量有所不同，此可能为正常大鼠和模型大鼠的药代动力学差异的原因之一。通过酒炙前后对脑缺血再灌注模型大鼠的药效学比较研究发现酒川芎给药组在降低脑梗死体积、NO含量等方面有较好的效果，结合谱效相关性分析发现酚酸类成分阿魏酸、水杨酸、绿原酸、香草酸、芥子酸、大黄酸以及内酯类成分洋川芎内酯A等为药效相关性成分，此时可以将川芎的功效物质基础再度缩减和明确为“活性化学成分群”。

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