交泰丸调控神经递质组织分布及其转运体功能治疗心肾不交失眠症的作用机制

Jiao Tai Wan (JTW) is a classical prescription which has definite effect in treating heart-kidney imbalance type of insomnia. However, its mechanism of action remains unclear. Based on the etiology of heart-kidney imbalance type of insomnia, insomnious neurotransmitters theory and characteristics of neurotransmitters tissue distribution and transportation combined with our previous study which investigates the tissue distribution and inhibitory effect on transporters of major components of JTW, we put forward with the hypothesis that the important therapeutic mechanism of insomnia is regulating neurotransmitter transporter function and improving disorder tissue distribution and abnormal transportation of neurotransmitters. Given this, the following experimental researches will be carried out. The distribution change of three types of neurotransmitters in brain, heart, kidney and liver will be investigated on an established insomnia rat model to confirm the pathogenesis of heart-kidney imbalance type of insomnia. At the same time, the regulating effect of JTW on the abnormal tissues distribution of neurotransmitters and function of its transporters will be investigated to interpret the therapeutic principle of keeping heart-kidney imbalance of JTW. This project would reveal the pathogenesis of heart-kidney imbalance of insomnia and action mechanism of JTW from the perspective of pharmacokinetics, based on the systemic regulation of endogenous substance at the molecular level. Its results will contribute to the study of molecular mechanism of syndrome in TCM. It also will provide research thought and experimental methods for action principle and compatibility rule of Chinese medicinal formulae. It has important theoretical value and practical significance for modernization of TCM.

交泰丸是治疗心肾不交失眠的经典名方，疗效确切，但机制至今不明。本课题针对心肾不交失眠病因、失眠的神经递质学说、神经递质组织分布及转运机制，结合前期交泰丸成分组织分布及对转运体抑制作用，提出调控神经递质转运体功能，改善递质组织分布及转运失调是交泰丸治疗失眠重要机制学说。鉴于此，本课题通过建立的心肾不交失眠大鼠模型，考察失眠状态下，三类神经递质在脑、心、肾、肝等组织的分布水平及其转运体的功能变化，确定心肾不交失眠的发病机制。综合分析交泰丸对神经递质分布失常的调整，以及对其转运体功能的调控，阐释交泰丸“交通心肾”治疗失眠的作用机制和药效物质。本课题从药动学角度，在分子水平，通过对内源物系统调控揭示心肾不交发病机制和交泰丸作用原理，有助于中医症候分子机制的研究，为中药方剂作用机制和配伍原理研究提供新的研究思路和实验方法，对中医药现代化具有重要的理论价值和实际意义。

针对“心肾不交”失眠病因以及交泰丸“交通心肾”治疗机制”问题，本项目提出了“调控神经递质转运体功能，改善递质组织分布及转运失调是交泰丸治疗失眠的机制”学说。研究过程中，采用PCPA建立了大鼠“心肾不交”失眠模型，结果发现“心肾不交”失眠状态下，围绕HPA轴相关组织（脑、心、肝、肾、肾上腺）中3类9种神经递质呈现分布紊乱的现象，交泰丸对此具有显著的改善作用；采用RT-PCR和western blot对神经递质转运体（经典和非经典转运体）基因和蛋白表达情况进行分析，结果表明，“心肾不交”失眠状态下，大鼠各组织转运体的表达出现了异常，交泰丸则显示明显的调控作用。在药效物质研究中，采用HPLC-MS/MS对交泰丸及其主要成分的体内暴露和代谢情况进行了分析，结果表明交泰丸主要成分可吸收入血并在体内产生广泛的代谢，生物碱及其多酚类成分可能是交泰丸的主要药效物质。 总之，本项目从药动学角度出发，以“方证相关”为指导，验证了外周神经递质与中枢系统疾病（失眠）的联系，初步揭示了“心肾不交”失眠症的实质和交泰丸作用原理。在此基础上，项目又进一步对相同证候不同病症（2-型糖尿病）的病因以及交泰丸的作用机制进行了探索，阐释了相同证候不同疾病之间的联系。项目体现了中医理论整体性和系统性的特征以及交泰丸多靶点、多途径治疗“心肾不交”失眠症的特点。