基于二维"组效关系"的柴胡疏肝散抗抑郁药效成分群及配伍规律研究

Depression is considered as a kind of critical disease which endangers the human being's health. The pathogenesis of depression is complex and the disease lacks of effective drugs for long-term treatment with low side-effect. Chaihu-Shu-Gan-San (CSGS) is a traditional Chinese medicine prescription (TCMP) with comfirmed effect in treatment of depression in clinic, however, its active basis is not clear and there has no systematic and comprehensive research on the compatible regularity of this prescription. Therefore, experiments to explore the antidepressive components and compatible regularity of CSGS would be designed to make a thorough research based on two-dimensional "Composition-Activity Relationship" research mode according to modern technologies and methods, whose core is metabolomic technique, combining pharmaceutical analysis, pharmacodynamics, statistical analysis and molecular biology. In this study, basing on the correlation of activity and components group, the antidepressive components group would be identified, the regulations of metabolic network related to compatible regularity of CSGS could be revealed, the action targets of active components group orginated from different funtional parts of prescription (monarch, minister, assistant and guide) would be investigated and classfied, and the difference of compatible synergism and single function could be described by the regulation of functional networks.This study will provide new ideas and evidences to identify the active components in TCMP and interpret the scientific nature of compatibility of TCMP. Furthermore,it will build stable foundation for the research and development of antidepressants and the modernization of TCMP.

抑郁症是危害人类身心健康的重大疾病，抑郁症发病机制复杂而临床缺乏可长期使用的有效、副作用小的药物。中药复方柴胡疏肝散临床用于治疗抑郁症疗效确切，然而其药效物质基础不明确、起效配伍规律未有系统深入的研究。基于此，本课题以柴胡疏肝散作为研究对象，以代谢组学技术为核心，结合药物分析、药理学、数理统计、分子生物学等学科的技术和方法，运用二维"组效关系"的研究思路对柴胡疏肝散的抗抑郁药效成分群及配伍规律进行研究。通过药效与成分组的关联性揭示柴胡疏肝散抗抑郁作用药效成分群，阐明其配伍过程中所调控的代谢网络，明确来源于不同功能单元（君、臣、佐、使）中的药效成分群所对应的作用靶点群，从功能网络调节角度说明配伍与单独使用的差异之处，为中药复方有效成分的辨识及中药复方配伍科学性的诠释提供新的思路及新的证据，进而为抗抑郁药物的研发及中药复方现代化的深入研究奠定坚实的基础。

抑郁症是危害人类身心健康的重大疾病，抑郁症发病机制复杂而临床缺乏可长期使用的有效、副作用小的药物。中药复方柴胡疏肝散临床用于治疗抑郁症疗效确切，然而其药效物质基础不明确、起效配伍规律未有系统深入的研究。基于此，本课题以柴胡疏肝散作为研究对象，以代谢组学技术为核心，结合药物分析、药理学、数理统计、分子生物学等学科的技术和方法，运用二维"组效关系"的研究思路对柴胡疏肝散的抗抑郁药效成分群及配伍规律进行研究。在本项目研究中，一方面，我们通过数学模型将宏观维度的药效指标与不同复方配伍化学组成液质联用数据进行关联分析筛选出12个潜在药效活性成分，通过药理模型验证了对药效贡献最大的成分-柚皮苷的药效活性，并深入研究了柚皮苷的抗抑郁作用机制；另一方面，明确了柴胡疏肝散抗抑郁作用起效的生物标志物群，锁定了微观维度的药效指标，从功能网络调节角度剖析复方的配伍规律，揭示了复方整体使用和缺味配伍的异同之处，基本阐明了柴胡疏肝散配伍规律；建立了基于二维“组效关系”思路的复方药效物质基础及配伍关系研究的方法，为中药复方有效成分的辨识及中药复方配伍科学性的诠释提供新的思路及新的证据，该方法可推广应用于天然植物药复杂体系作用机制阐明及活性成分发现的研究当中。