银丹心脑通软胶囊“心脑同治”质量控制指标选择与质控新模式探索研究

In Chinese medicine, “the same treatment for different disease” is a characteristic application of traditional Chinese medicine (TCM) in the clinic. How to select the markers represented the multi-bioactivities is still the key problem in quality control of TCMs. Yindan Xinnaotong Capsule (YXC) is widely used to treat cardiovascular and cerebrovascular disease, the efficacy is called as “heart-brain concurrent regulation”. In this project, taking YXC as an example, we will develop a new strategy based on “forward selection stepwise regression- multi-dimensional pharmacodynamics evolution” to select the combinatorial markers for TCM quality control. This project includes four components: (1) The comprehensive chemical profiling and metabolic disposition research; (2) The High-Content Screening technique will be applied to acquire the multi- and dynamics parametric data (representative the heart and brain protection) of the components from YXC, the forward selection stepwise regression and multi-dimensional pharmacodynamic evaluation will be established, and applied for the combinatorial markers of heart-brain concurrent regulation (HBCRCCs) screening; then the efficacy of HBCRCCs will be confirmed in vivo; (3) Expounding the interaction modes and mechanism according to the endogenous network regulation and injured mitochondria protection; (4) A new quality control method of YXC will be developed based on the quantity-effect relationship of HBCRCCs. The research strategy proposed here will provide a new thought and methodological support for the quality control mode of TCM with multi- integrative effects.

“异病同治”是中药复方临床应用特色之一，如何选择与“异病同治”药效关联的质控指标是中药复方质量评价领域的关键科学问题。本项目拟以“心脑同治”的银丹心脑通软胶囊为载体，建立“向前逐步选择法-多维药效指标共评价”的药效成分组合筛选方法，探索具有“异病同治”作用的中药复方质量控制新模式。具体如下：（1）解析银丹心脑通软胶囊化学成分及体内代谢过程；（2）以高内涵细胞成像评价各成分及组合在心、脑保护作用中的多重、动态药效，基于“向前逐步选择法”和多维药效指标共评价模型筛选“心脑同治”成分组合，并以小鼠模型进行药效验证；（3）从整体代谢网络调控和线粒体损伤保护两方面，探讨“心脑同治”作用机制；（4）基于“心脑同治”药效成分组合的量效关系，建立与临床疗效相关联、以“心脑同治”成分组合为标示的质量控制新方法。本项目以“心脑同治”中药开展示范性研究，为探索具有多效性中药的质量控制模式提供新的思路与方法支撑。

本项目以银丹心脑通软胶囊为研究对象，（1）利用UHPLC-QTOF MS和GC-MS方法，发展了结合质量亏损过滤、中性丢失和特征碎片的快速筛选策略，开展了银丹心脑通软胶囊软胶囊体内外化学成分表征，从银丹心脑通软胶囊中鉴定124个化学成分，从大鼠血浆中鉴定29个原型成分和93个代谢成分，并对15个原型成分开展了血浆药代动力学研究；（2）分别构建了LPS诱导的小鼠小胶质瘤细胞BV2神经炎症M1/M2极化状态表征的高内涵筛选模型，以及基于细胞膜色谱（CMC）的小鼠心肌细胞H9C2/CMC-C18 2D LC-MS筛选模型等，开展多维药效评价并快速筛选得到银丹心脑通软胶囊中脑、心保护的活性成分及组合；（3）通过网络药理学、转录组学、cMap、分子对接等手段，探索了银丹心脑通软胶囊“心脑同治”整合调节机制，部分揭示了银丹心脑通软胶囊协同成分组合（黄酮类与丹参酮类、野黄芩素+丹参酮I、野黄芩苷等）的相互作用模式及潜在作用机制；（4）在上述基础上，构建了银丹心脑通软胶囊的指纹图谱及多成分含量测定方法，为其质量评价提供了数据及技术支撑。研究结果在Phytomedicine、Journal of Chromatography A等已发表论文5篇，培养博士研究生1人，硕士研究生4人。