从“蛋白质-代谢”网络药理学研究柴胡疏肝散抗抑郁的配伍寻优

There are several disadvantages difficult to overcome for antidepression with western medicine, fortunately Chinese medicine to treat depression got more and more attention because of its "multi-target" efficacy and less side effects. We have pre-confirmed: Chaihu-Shugan-San (CHSGS) performed better antidepression than its demolition by regulating MAPKs signaling pathway and inhibition of the HPA axis hyperactivity. However, it is impossible to explain the overall effects of CHSGS as a whole formula, and it exists the lack of network pharmacology, thus above problems become the key scientific issues of this project. Accordingly, based the Chinese theory “whole concept” and network pharmacology thinking, we propose a hypothesis that the overall antidepressant efficacy of CHSGS refers to network regulation of proteins- metabolites. To confirm this hypothesis, based on the idea of network pharmacology, the project aims to apply quantitative proteomics-metabolomics technology to study antidepressant effect and the overall compatibility of the active ingredient group of CHSGS. to compare the overall effect and the effect of the demolition party to obtain a multi-target antidepressant network diagram and its anti-depressive compounds, according to the "omics" angle, to offer the evidence of better effects of CHSGS compared with theoretical basis demolition. This study will help to reveal the compatibility superiority of antidepressant effects of “Jun-Chen-Zuo-Shi” based CHSGS, to obtain absorption spectra of its efficacy target components, and to show an innovative new ideas for the basic research of traditional Chinese formula.

西医治疗抑郁症存在诸多难以克服的缺点，中医药以其“多靶点”和副作用小的优势越来越受到重视。我们前期已证实：柴胡疏肝散通过调节MAPKs信号通路和抑制HPA轴亢进发挥优于其拆方的抗抑郁作用。然而，其不能说明柴胡疏肝散配伍寻优的整体疗效，缺乏网络药理依据，因而成为本项目的关键科学问题。据此，我们基于中医整体观和网络药理学思想，提出柴胡疏肝散抗抑郁的整体疗效涉及蛋白-代谢分子群的网络调控。为证实这一假说，本项目拟从网络药理学角度，应用定量蛋白质-代谢组学技术，对柴胡疏肝散抗抑郁的配伍效应及其整体活性成分群进行研究，比较全方与基于治法进行拆方的整体疗效，获得其抗抑郁的多靶调整网络图及抗抑郁的活性靶成分群，从“组学”角度提供柴胡疏肝散整体疗效优于其拆方的理论依据。本研究将有助于揭示柴胡疏肝散“君臣佐使”抗抑郁的配伍优越性，明确其药效吸收靶成分谱，创新中药复方基础研究的新思路。

西医治疗抑郁症存在诸多难以克服的缺点，柴胡疏肝散以其“多靶点”和副作用小等显示出中医药的优势治疗特色。但是，柴胡疏肝散治疗抑郁症的配伍优势、潜在靶点与通路有待阐明。为阐释柴胡疏肝散配伍寻优的整体疗效，我们基于网络药理学手段，并应用定量蛋白质组学-代谢组学技术，对柴胡疏肝散抗抑郁的配伍效应进行研究，比较全方与其拆方（疏肝组、柔肝组）的整体疗效，获得其抗抑郁的多靶点调控网络图，提供柴胡疏肝散整体疗效优于其拆方的基础理论依据。整体疗效实验证实：与拆方组比较，总方组明显改善抑郁症模型大鼠行为学，与氟西汀疗效相当。网络药理学-定量蛋白质组学-代谢组学联合分析显示：与拆方组比较，总方组通过显著下调Gad2和Vamp2等22个蛋白，靶向γ－氨基丁酸（GABA）的合成、释放、再摄取和降解通路，发挥总体抗抑郁疗效优势。柴胡疏肝散抗抑郁的潜在通路主要涉及突触传递、白介素信号、CaMKII激活和多种神经递质释放（GABA、乙酰胆碱、5-羟色胺、去甲肾上腺素、多巴胺和谷氨酸等），其药理作用模式优于拆方组。本研究将有助于揭示柴胡疏肝散整体抗抑郁的配伍寻优性，创新中药复方配伍基础研究的新思路。