黄连温胆汤调控神经胶质细胞免疫代谢的抗抑郁分子机制研究

The incidence of depression is high, but the antidepressant drugs are relatively scarce. The classical prescription on Chinese materia medica, Huanglian Wendan decoction, is effective in clinical treatment of depression, there is still an urgent need of basic research to promote. We have observed the glial immunological inflammation in functional brain area of chronic stress induced depressed animals, and then found in stress hormone (corticosterone) treated glial cells the immunometabolic changes as the new research growth point. We hypothesize that the changes of neuroglial immunometabolism is the key basic biological event in stress-induced depression. Based on previous work of confirming the amelioration of depressive behavior and neuroinflammation in depressed animals by Huanglian Wendan decoction, it is hypothesized that the Huanglian Wendan decoction could regulated the immunometabolism therefore prevent and treate depression. In the study, we focus on the changes of neuroglial immunometabolism in functional brain area, exploring the characteristics and laws of stress (or stress hormone) and drug intervention induced changes of neuroglial immunometabolism at the level of cell (microglia and astrocyte), organelle (mitochondria) and molecular (immunometabolic component and signal such as TXNIP, NLRP3, etc.). The most important target of the study is to clarify the function characteristic and molecular mechanism of prevention and treatment of depression by Huanglian Wendan decoction through regulating glial immunometabolism in functional brain area. And to provide experimental basis for clinical prevention and treatment of depression by Huanglian Wendan decoction.

抑郁症高发而抗抑郁药物相对匮乏，经典方黄连温胆汤临床有效治疗抑郁症但亟需基础研究推动。本项目组在慢性应激诱导的抑郁症动物模型上观察到功能脑区神经胶质细胞免疫炎症，继之初步证实应激激素皮质酮诱导神经胶质细胞免疫代谢改变，以此为研究新生长点，创新提出神经胶质细胞免疫代谢改变可能是慢性应激引起抑郁症发生和发展过程中的关键基础生物学事件；立足黄连温胆汤改善动物抑郁样行为和功能脑区神经炎症的工作基础，进一步提出该方通过调控神经胶质细胞免疫代谢而防治抑郁症的工作假说。本项目聚焦功能脑区神经胶质细胞免疫代谢，从细胞（小胶质和星形胶质细胞）、细胞器（线粒体）、免疫代谢相关组件和信号分子（如TXNIP、NLRP3）等水平探询慢性应激及皮质酮引起神经胶质细胞免疫代谢改变的特征和规律；重点研究并阐明黄连温胆汤调控功能脑区神经胶质细胞免疫代谢的抗抑郁分子机制和作用特色，为其临床防治抑郁症提供实验基础。

抑郁症高发而抗抑郁药物相对匮乏，经典方剂黄连温胆汤临床有效治疗抑郁症但亟需基础研究推动。本研究基于前期工作基础，提出黄连温胆汤方通过调控神经胶质细胞免疫代谢而防治抑郁症的工作假说。本研究首先基于黄连温胆汤水提物实测成分开展网络药理学分析研究，进一步明晰黄连温胆汤抗抑郁的有效成分和潜在靶标信息；在此基础上按研究计划完成动物/细胞模型的实证研究，聚焦功能脑区小胶质细胞和星形胶质细胞的免疫代谢变化，研究以阐明黄连温胆汤调控功能脑区神经胶质细胞免疫代谢的抗抑郁分子机制和作用特色；完成2个主题研究：①基于小胶质细胞精氨酸代谢调控发现黄连温胆汤抗抑郁成分及其作用机制研究②基于星形胶质细胞TXNIP表达调控发现黄连温胆汤抗抑郁成分及其作用机制研究；针对原创发现机制分子靶标，建立功能细胞用于筛选调控神经胶质细胞免疫代谢的新型抗抑郁中药。为黄连温胆汤及其有效成分临床防治抑郁症提供实验基础。