孕酮、四氢孕酮对PMDD肝气逆证模型大鼠关键脑区中GABA功能的调控机制研究

Premenstrual Dysphoric Disorder (PMDD) is the severe form of Premenstrual Syndrome (PMS). The wemen with PMDD might appear the tendency to commit suicide or attack behavior, which affected the family stability and social harmony.But its pathogenesis were still unclear.Our preliminary studies found that PMDD key aspects closely related to brain. FMRI imaging studies further cleared activated brain regions. Other studies suggest that progesterone and its metabolic products ALLO exception is the new hotspot in the research of the pathogenesis of PMDD. More clinical studies suggest that progesterone can pass GABA and its associated system to involve in emotion regulation, and leads to susceptibility to bipolar disorder。Therefore we concluded that the regulation of P and its metabolites ALLO to GABA function in specific brain regions could be PMDD Liver-qi Invasion pathogenesis. This project intended to detect level of progesterone ,ALLO and GABA functional changes. At the same time,we further revealed the regulation mechanism of progesterone, ALLO to GABA function for PMDD etiology. We would deeply reveal central mechanisms for liver pathogenesis , and rich the scientific hypothesis " functional regulation of liver controlling dispersion was focus on specific brain regions". Thus innovate liver visceral manifestation theory of traditional Chinese medicine .The above was expected to make contribution of traditional Chinese medicine for the difficulty of modern medical knowledge emotional disorder.

PMDD是PMS的严重类型，可出现自杀倾向或攻击行为，影响家庭稳定、社会和谐,但其发病机制尚不清楚。我们前期研究发现PMDD发病关键环节在脑中枢，fMRI影像学研究进一步明确激活脑区。孕酮及其代谢产物四氢孕酮异常是PMDD病机研究的国际新热点。临床研究提示，孕酮（P）、四氢孕酮（ALLO）可通过GABA系统参与情绪调节，并导致情感障碍的易感性。据此我们推断：P及其代谢物ALLO变化调控特定脑区GABA功能是PMDD肝气逆证的关键机制。本项目拟以PMDD肝气逆证模型大鼠为研究对象，通过检测模型大鼠关键脑区P、ALLO及GABA功能变化，并采用孕酮受体及GABAA受体拮抗剂干预，进一步揭示PMDD病因学中P、ALLO对GABA功能的调控机制。深层揭示肝疏泄失常发病中枢机制，丰富“肝主疏泄功能调控在中枢特定脑区”的科学假说，从而创新肝藏象理论。有望为现代医学认识情感障碍性疾病难点做出中医学的贡献

PMDD是PMS的严重类型，可出现自杀倾向或攻击行为，影响家庭稳定、社会和谐,但其发病机制尚不清楚。我们前期研究发现PMDD发病关键环节在脑中枢，fMRI影像学研究进一步明确激活脑区。孕酮及其代谢产物四氢孕酮异常是PMDD病机研究的国际新热点。临床研究提示，孕酮（P）、四氢孕酮（ALLO）可通过GABA系统参与情绪调节，并导致情感障碍的易感性。本项目研究结果显示PMDD肝气逆证大鼠血清中ALLO显著降低，下丘脑中ALLO也显著降低，同是，血清及下丘脑、前额叶皮质中GABA显著降低，同是下丘脑及杏仁核中GABAARα4亚基表达降低，全细胞膜片钳结果显示氯离子通道电流降低，从分子及细胞层面说明ALLO孕酮的降低，会引起外周及中枢GABA含量下降，降低GABA系统的抑制作用，是PMDD肝气逆证重要发病机制。为进一步验证，通过ALLO及非那雄胺干预PMDD肝气逆证模型大鼠，发现给与ALLO后确能改善模型大鼠一系列异常表达，给与5α还原酶抑制剂非那雄胺后在行为学、分子及细胞生物写方面确能表现出与PMDD肝气逆证模型大鼠类似的表现。进一步说明PMDD肝气逆证发病机制与ALLO及其介导的GABAAR功能关系密切，也验证了本项目初步提出的科学推断：P及其代谢物ALLO变化调控特定脑区GABA功能是PMDD肝气逆证的关键机制。丰富“肝主疏泄功能调控在中枢特定脑区”的科学假说，从而创新肝藏象理论，为后期新药研发提供理论基础。