基于“组分-药效-毒性”调控内源性代谢研究四逆汤配伍机制

Sini Decoction is a famous formula from 'Shang Han Za Bing Lun' which is praised as the first formula of reviving yang for resuscitation. Experimental study on early research found that the content of aconitum diester-diterpenoid alkaloids as aconitine (C34H47NO11) decreased, while the monoester form as benzoylaconitine (C32H45NO10) increased, after Sini Decoction was compatible and decocted with other drugs; and compared with the Fuzi-Ganjiang herb pairs and Fuzi-Gancao herb pairs, Sini Decoction has a more stronger effect on rat model of myocardial infarction (MI), which means we probe into the “improve effect and decrease toxicity” mechanism from two aspects of effect difference in efficacy and toxic composition change. However, we still need to further explain the meaning of the prescription's connotation and compatibility mechanism of “rescuing from collapse by restoring Yang” from the biological endogenous substance network regulatory mechanism. The project stands on the Sini Decoction can reduce the herb's cardiac toxicity and improve animal cardiogenic shock, and puts forward the viewpoint that “build correlation of ‘ingredient-efficacy-toxicity’, study the compatibility mechanism of Sini Decoction regulating endogenous metabolic network”. The project uses the cardiac function theory, histopathology and molecular mechanism to study the cardiotonic effect mechanism, uses the metabonomics and heart target organ proteomics technology to interprets the endogenous network regulatory mechanism of “rescuing from collapse by restoring Yang” from the overall effect level, and reveals the compatibility mechanism of Sini Decoction.

四逆汤为仲景名方，被誉为“回阳救逆第一方”。课题组前期实验研究发现，四逆汤配伍合煎后其毒性成分乌头碱（C34H47NO11）等双酯型生物碱含量降低，而药效成分苯甲酰乌头原碱（C32H45NO10）等单酯型生物碱含量升高；且四逆汤改善心肌梗死（MI）大鼠的心肌梗死范围的作用强于附子-干姜、附子-甘草药对，从毒效成分变化及药效差异两层面探讨了该方“增效减毒”的配伍机制，但仍需进一步从机体生物性内源物质网络调控机制诠释其“回阳救逆”的组方内涵与整方配伍机制。本项目以四逆汤减轻药物心脏毒性和改善动物心源性休克为切入点，提出“构建‘组分-药效-毒性’相关性，研究四逆汤调控内源性代谢网络的整方配伍机制”的观点。采用心脏功能学、组织病理学和分子机制研究手段探索其抗心衰作用机制，并联用机体整体代谢组学和心脏靶器官蛋白质组学技术，从整体效应层面诠释其“回阳救逆”组方的内源性网络调控机制，揭示四逆汤配伍机制。

四逆汤为临床经典急救方，迅达救逆回阳之功，药味精简，组方精妙。本课题以四逆汤减轻药物心脏毒性和改善动物心源性休克为效应点，针对中药作用的整体性，构建了四逆汤药味间‘组分-药效-毒性’相关性模型，以挖掘其组方内涵及整方配伍机制。课题采用大鼠在体肠灌注模型，研究四逆汤配伍前后，药效成分在体内的吸收差异，探究四逆汤的在体肠吸收状况，为探究四逆汤毒效表达奠定了基础；采用网络药理学方法，成功构建附子抗心衰作用与心脏毒性的“成分-靶点-通路”生物网络；采用大鼠心力衰竭模型，研究四逆汤配伍前后抗心衰生物效应表达；并考察四逆汤对正常大鼠的毒性，研究四逆汤配伍前后对心脏的毒性作用；拓展性研究附子多糖对机体的免疫调节作用，确定了附子多糖的分子结构，并发现附子多糖除抗氧化作用外，还可通过上调免疫功能，有效缓解大鼠慢性腹泻。从整体效应层面诠释了四逆汤“回阳救逆”组方的网络调控机制，揭示四逆汤的整方配伍机制。