基于“预期效应—实际效应”函数模型解析逍遥散功能药队抗抑郁配伍规律

The antidepressant effects of Xiaoyaosan (XYS), a classic prescription, have been confirmed. It has been unanimously approved to reveal the compatibility principles of XYS from the perspective of efficacy compositions. However, the present studies just stay on simple and descriptive characterization, which are still in lack of quantitative and in-depth information and fail to demonstrate and analyze the scientific connotation of the compatibility principles of XYS accurately. In the current research, we will combine the quantitative analysis by using mathematical methods and the evaluation of drug efficacy. We will divide the XYS prescription into two efficacy compositions, i.e. Shugan and Jianpi compositions. And then, we will investigate the effects of XYS, Shugan and Jianpi compositions on the symptoms of depression. Afterwards, taking the antidepressant indicators as parameters, we will first calculate the expected effects, i.e. the theoretical value under the assumption that no interaction effect occurs. And then, the mathematical relationships and the function models of "Expected effect – Experimental effect", as well as the 2D graphs, will be constructed to quantitatively characterize the contribution of the two efficacy compositions to XYS's antidepressant effect, and to deeply understand the interactions between the two efficacy compositions. The results of the current project will not only manifest accurately the compatibility principles of XYS, but also establish a research method, which follows the basic rules of the dose-effect relationship and meets the characteristics of prescription compatibility (e.g. systematicness, integrity, complexity) and the assemblage features of pharmaceutical effects, as well as a research model by means of using specific parameters, concise formulas and statistical analysis. Overall, the current project is of significance in both theory and practice in terms of exploring the scientific connotation of compatibility principles of TCM prescription, and of promoting the modernization of TCM, as well as of guiding the creation of new drugs.

经典名方逍遥散已被证实具有确切的抗抑郁作用。从功能药队理解该方的配伍关系已获得一致认同。然而，目前对逍遥散配伍关系的研究仍停留在简单的描述性表征上，缺乏定量化的深入研究，不能准确地解析其配伍的科学内涵。本项目拟将数学定量方法与药效评价相结合，将逍遥散拆分为疏肝与健脾两个功能药队，考察各药物组干预抑郁症的药效；以这些药效指标为参数，计算零相互作用的理论值，即预期效应，并构建“预期效应—实际效应”函数模型和二维图，量化表征各功能药队对逍遥散抗抑郁药效的贡献及其相互作用。研究结果不仅能准确解析逍遥散抗抑郁配伍关系，而且有望建立一种既遵循药物量效关系的基本规律、药效的集合特征，又符合复方配伍系统性、整体性、复杂性等特点的数学方法，以及一种应用具体的参数、简洁的公式和统计的方法准确解析复方配伍规律的研究新模式。项目对探索中药配伍科学内涵、推动中药现代化和指导创制新药具有重要的理论和应用意义。

本项目在中药配伍理论的指导下，引入数学思维，将数学定量方法与药效评价相结合，针对“逍遥散抗抑郁配伍关系不明确”这一科学问题，开展了系统研究。首先，基于功效药队分析策略，将逍遥散拆分为疏肝和健脾两个药队，考察逍遥散、疏肝、健脾的抗抑郁药效作用。结果表明，三组均能显著改善抑郁大鼠的核心症状和伴发症状，逍遥散作用最强。其次，基于药效学数据，构建“预期效应-实际效应”函数模型，应用此模型定量表征了疏肝和健脾药队的协同作用。然后，引入模糊数学理论，应用粗糙集定量表征了两个药队的配伍关系。同时，应用路径分析方法计算了两药队对逍遥散抗抑郁药效的贡献。研究结果表明逍遥散功效药队各有侧重、相辅相成，协同发挥抗抑郁作用，体现了逍遥散配伍的科学性和合理性。最后，应用代谢组学和网络药理学技术从代谢物层面和分子层面揭示了逍遥散抗抑郁配伍机制。研究结果显示，健脾药队与疏肝药队在剂量13.88-46.06g/kg之间呈现协同抗抑郁效应,在46.06-72.51g/kg呈现相加效应。尿液代谢组学研究表明，三组显著调节了3-甲基组氨酸和泛酸的水平，涉及组氨酸代谢和谷胱甘肽代谢。此外，逍遥散显著调节丙酮酸和马尿酸的含量，表明其可以调节糖酵解/糖异生和苯丙氨酸代谢，回调指数值的顺序是XYS (2013.86) > SG (1951.81) > JP (1899.56)。逍遥散组效果最佳。基于16sRNA基因序列技术的肠道微生物组学研究发现，各组有差异地调节不同物种的丰富度。Spearman相关分析结果显示，科水平上Corynebacteriaceae, Staphylococcaceae和Brevibacteriaceae，属水平上Sporosarcina，Brevibacterium和Macrococcus与行为学结果显著相关。各给药组对科水平的回调程度：疏肝组>逍遥散组>健脾组；对属水平的回调程度：逍遥散组>疏肝组>健脾组。研究结果以精准的数学语言解析了逍遥散抗抑郁配伍关系，丰富了逍遥散配伍理论的科学内涵，而且为诠释中药配伍科学内涵提供了新思路，为指导新方配伍及其创制新药探索了一条切实可行的路径。