基于Glu-mGluR2/3介导的海马NVU联动损伤研究糖尿病并发抑郁症发病机制及中药干预

The pathogenesis of diabetes mellitus with depression (DD) is concealed and easily repeated attack with a high mortality rate. However, its mechanism is not clear yet. Our previous research found that a structural modification and a function decline in astrocytes (As) and microvascular (Ve) were closely related to another receptor of glutamic (mGluR2/3) after we defined that the damage of hippocampus and abnormal expression of ionotropic glutamate receptors were the main target location in DD. Furthermore, glutamic is regarded as ‘a signal messager’ in neurovascular unit which consists of neuron, Ve and As. On the base of previous study, we believe that Glu-mGluR2/3 mediated NVU linkage damage is an essential element that leads to DD. Consequently, this research intends to further investigate a molecular mechanism of DD which associated with an increased permeability of Ve, a disordered regulation of glutamic by As and Glu-mGluR2/3 mediated linkage damage of NVU on the aspects of in vivo-in vitro and morphology-function-molecular level by the methods including patch clamp, high content analysis, flow cytometry and liquid chromatography-mass spectrometry techonology. The theory of “enriching yin and nourishing qi, disperse blood stasis and resolve depression” was applied to disproof the pathology (asthenia, stasis, depression) of DD, which provide a new ideas for the research of its pathogenesis and the prevention.

糖尿病并发抑郁症（DD）发病隐匿、易反复且致死率高，但其机制未明。课题组在首次明确海马损伤和谷氨酸受体NR表达异常分别是DD发生的关键靶部位和靶点后发现，DD大鼠海马星形胶质细胞（As）和微血管（Ve）发生了结构改变和功能衰退，并与谷氨酸另一种受体 (mGluR2/3)密切相关。谷氨酸在由神经元、Ve、As构成的功能整体——神经血管单元（NVU）中扮演了“信号使者”角色。结合前期基础，我们提出：Glu-mGluR2/3介导的NVU联动损伤是DD发生、发展的重要环节。本课题组拟采用膜片钳、HCS、FCM和液质联用等技术，从在体-离体两方面、形态-功能-分子三水平，探明“Ve通透性增加，As调控谷氨酸障碍，通过Glu-mGluR2/3介导海马NVU联动损伤，进而诱发DD ”的分子机制，并采用“滋阴益气、化瘀解郁”立法方药干预反证DD“虚、瘀、郁”中医病机，为其发病机制和有效防治研究提供新思路。

糖尿病并发抑郁症（DD）继发于糖尿病，具有发病隐匿、易反复、致死率高等特点，然其确切发病机制至今尚未阐明。课题组在首次明确海马损伤和谷氨酸受体NR表达异常分别是DD发生的关键靶部位和靶点后发现，DD大鼠海马星形胶质细胞（As）和微血管（Ve）发生了结构改变和功能衰退，并与谷氨酸另一种受体(mGluR2/3)密切相关。由神经元、As、Ve共同组成的神经血管单元（NVU）富含谷氨酸受体，而谷氨酸在NVU的损伤中扮演了“信号使者”角色。本研究推测：Glu-mGluR2/3介导的NVU联动损伤是DD发生发展的关键病因病机。.本研究以STZ（i.v,38mg/kg）联合28d CUMS诱导的DD动物模型和高糖（150mM）联合皮质酮（200μM）诱导的DD细胞模型为研究对象，分别从体内、体外两方面，探讨Glu-mGluR2/3介导海马NVU联动损伤进而诱导DD的分子机制以及益气滋阴、化瘀解郁的中药复方左归降糖解郁方的干预机制。研究表明，糖尿病状态下，Ve通透性增加，As调节谷氨酸障碍，Glu-mGluR2/3信号明显激活，调控其下游GR-ERK-GDNF及GFR-PI3K-AKT通路异常而介导海马NVU各组分间信息传递异常、结构功能改变，诱导DD发生；而左归降糖解郁方能够通过调控Glu-mGluR2/3及其相关信号通路保护海马NVU，从而发挥治疗DD的作用。.综上，本研究阐明了“虚、瘀、郁”病机状态下，Glu-mGluR2/3介导海马NVU联动损伤，诱发DD的分子机制，明确了左归降糖解郁方治疗DD的作用环节及潜在靶点，为DD的中医药防治研究提供了理论依据。