神经递质/蛋白调控双模式关联的五味子酒制“宁心安神”中枢系统作用机制研究

Schisandra chinensis (Turcz. ) Bail was classified as top grade in traditional Chinese medicine (TCM) with efficacies of astringing lung, promoting fluid production, relieving diarrhea, and tranquillization. Among them, the effect of tranquillization got the favor of the ancient physicians. In the long-term clinical practice, TCM physicians found that Schisandra processed with wine has a unique advantage in the effect of tranquillization. Since the Song Dynasty, some processing theory formed such as “wine soaked through, to assist the efficacy”. Currently, this efficacy got heritage, meanwhile the application of processing varieties for Schisandra was confusion. The advantages and characteristics of Schisandra processed with wine had not been fully appreciated. There is still blank about the study on the tranquillization effect mechanism which is closely related with central nervous system..Based on the existing research foundation, a dual mode method of neurotransmitters-protein regulation is proposed innovatively. Besides, comparative proteomics of nervous cells was firstly introduced to the study of the TCM processing mechanism. Three aspects “seeking of active ingredients group, detection of bioactive ingrediens and exploring of protein regulation targets” were combined to illuminate the scientific connotation of tranquillization for Schisandra. The research will provide a theoretical basis for the use of Schisandra with accurate, reliable, and objective data. Furthermore, this study will be helpful to inherit and carry forward the therapeutic advantage of Schisandra.

五味子，列为上品中药，具有敛肺、生津、止泻、安神之功。其宁心安神作用得到历代医家青睐。中医在长期临床实践中，早已发现五味子酒制品在这一功效发挥上具有独特优势，自宋代形成了五味子“酒浸行经，以襄药效”等炮制理论。然而目前，在对五味子药材这一功效传承沿用的同时，却忽视了对其炮制品种的应用，酒五味子的优势和特色未得到充分认识，该炮制品种安神作用机制的研究尚为空白。五味子宁心安神关键机制与中枢神经系统作用相关，本课题组已有研究基础。项目创新性的提出神经递质-蛋白调控双模式研究方法与新技术，并将神经细胞比较蛋白质组学首次引入中药炮制机理的研究中。实现效应化学成分群寻找--效应部位生物活性成分时量变化--相关蛋白调控靶点探索的“三位一体”研究思路，全面阐述酒五味子宁心安神的科学内涵。用准确可靠，科学客观的数据为酒五味子合理应用提供理论依据，从而为更好的继承和发扬这一传统炮制品种的优势奠定基础。

本课题以酒制五味子为研究对象，围绕其在宁心安神方面的独特作用与作用机制进行了深入的研究。通过建立南、北五味子的快速鉴定识别模式，确认北五味子品种；通过对五味子炮制前后（酒品、醋品）移行成分的研究，从化学成分的角度揭示五味子的炮制机制与酒制品的效应物质；通过对酒五味子入血，入脑化学成分的识别追踪，确认了酒五味子通过血脑屏障到达中枢系统发挥作用的物质基础主要为12种木脂素类成分；建立UPLC-QTOF-MSE和UPLC-QTOF-MRM（Enhanced Target）的综合定量研究策略，获得了酒五味子中枢作用的体内药代动力学规律，结果显示相比于五味子生品，酒制品中木脂素类成分的吸收更为显著，系统暴露更高，均可以透过血脑屏障，在脑中消除较快。采用谷氨酸诱导的HT22神经细胞，揭示了酒五味子进入中枢系统木脂素有效成分的神经细胞整体保护作用，并对所调控的细胞蛋白进行探索，发现了与细胞代谢相关，和激素，神经内分泌相关的蛋白。 .通过对上述研究内容的积极开展，本课题实现了对酒五味子宁心安神的物质基础，体内作用规律与神经细胞的作用机制的探索，为酒五味子合理应用提供理论依据，为更好的继承和发扬这一传统炮制品种的优势奠定基础。