淫羊藿黄酮类成分调控下丘脑神经炎症改善CUMS大鼠糖耐量的机制研究

The risk of depression with comorbid type 2 diabetes is increased in modern society, therefore it is in urgent need of the effective preventive or treatment modalities. Based on our prior work and new findings, this project will focus on the central hypothalamic neuroinflammation, and investigate the pathological changes of hypothalamic neuroinflammation during the chronic unpredictable mild stress (CUMS) process, resulting in the impaired glucose tolerance in rats. This project will explore the molecular pathological mechanisms by which the hypothalamic neuroinflammation, as the key pathological aspect, disturbs hypothalamic insulin signaling, subsequently causing glucose intolerance and increased risk of comorbid type 2 diabetes in depressed CUMS rats. These will provide the scientific interpretation of emotional imbanlance-caused Xiao Ke (consumptive thirst). Then, it is proposed to treat the emotional imbalance-caused Xiao Ke from kidney. This project is to investigate systematically the prevention and treatment of glucose intolerance in depressed CUMS rats by the flavonoids of Epimedium, one of the warm and tonify kidney-yang herbs. The integral pharmacological effect and molecular mechanism by Epimedium flavonoids are to be studied, importantly the regulation of hypothalamic neuroinflammation in CUMS rats and the subsequent improvements in hypothalamic insulin signaling and glucose tolerance of the depressed animals. Moreover, this study will be helpful in providing experimental basis for the prevention and treatment by Epimedium flavonoids of comorbid type 2 diabetes in depression patients. Additionally, it is also helpful to support the scientific interpretation of emotional imbalance-caused Xiao Ke and the scientificity of treating the emotional imbalance-caused Xiao Ke from kidney, basing on the traditional Chinese medicine thinking “therapeutic effects verify pathogenesis”.

现代社会抑郁症共病2型糖尿病风险升高，寻求有效防治措施成为医药界亟待解决的问题。基于前期工作基础与新发现，本项目以下丘脑神经炎症为切入点，研究其在慢性不可预期温和应激（CUMS）引发大鼠糖耐量受损过程中的病理变化特征；探询下丘脑神经炎症作为关键病理环节，诱导下丘脑胰岛素信号转导异常引起CUMS大鼠糖耐量受损的分子病理机制；以科学诠释“情志失调致消渴”。继之，从肾论治情志失调所致消渴，系统研究温补肾阳中药淫羊藿黄酮类成分调控下丘脑神经炎症，继而保护和改善下丘脑胰岛素信号转导以预防和治疗CUMS大鼠糖耐量受损，降低该抑郁症模型动物共病2型糖尿病风险的完整药理作用与分子机制；兼以分析淫羊藿黄酮类成分干预神经炎症可能的多靶点调控优势与机制。为温补肾阳中药临床防治抑郁症共病2型糖尿病提供实验证据的同时，基于中医药“以效证因”思维佐证“情志失调致消渴”的科学内涵以及从肾论治情志失调所致消渴的科学性。

抑郁症共病二型糖尿病风险高而机制不明，更为严重的是临床防治药物相对匮乏。针对此，本项目在探究其共病机制基础上针对性开展药物筛选和机制研究。本项目在明晰CUMS大鼠抑郁样行为合并糖耐量受损病理特征基础上，以抑郁模型动物糖耐量受损关键病理环节——下丘脑神经炎症为研究切入点，探询CUMS大鼠下丘脑神经炎症在其糖耐量受损慢性病程中的病理变化特征与分子病理机制，揭示以IL-1β表达及活化异常升高为特征的神经炎症介导下丘脑胰岛素信号转导受损。本项目在病理研究基础上，建立并优化体外小胶质细胞病理模型，选择温补肾阳中药淫羊藿黄酮类成分开展活性筛选及干预研究，筛选发现具有抗神经炎症活性的淫羊藿黄酮类成分，值得提出是，本项目基于体外初筛获得候选药物（淫羊藿苷和宝藿苷Ⅰ）在体活性作用差异深入探索其机制差异，最终发现淫羊藿苷主要通过抑制小胶质细胞NLRP3炎症小体表达与活性这一抗神经炎症关键环节而有效改善糖耐量的分子机制。上述主体工作基础上，进一步拓展研究发现应激诱导的星形胶质细胞TXNIP-NLRP3神经炎症以及神经元TXNIP损害胰岛素信号的新分子机制，并继之研究淫羊藿黄酮类成分的干预作用，揭示淫羊藿黄酮类成分改善抑郁并发糖耐量受损的多靶标作用特色和优势。综上，本项目研究揭示了慢性应激诱导下丘脑神经细胞TXNIP和NLRP3表达及活性异常，引发胶质细胞神经炎症并损害下丘脑神经元细胞胰岛素信号转导，引发抑郁并发糖耐量受损的病理机制，为抑郁症共病2型糖尿病风险升高提供了新的中枢病理解释，为诠释情志失调致消渴提供科学依据。本项目筛选研究发现的淫羊藿苷和宝藿苷Ⅰ等淫羊藿黄酮类成分的有效作用及分子药理机制，佐证病理研究结果的同时为淫羊藿黄酮临床防治抑郁症共病2型糖尿病提供了实验基础，也为应用温补肾阳类中药从肾论治情志失调所致消渴策略提供了证据和支撑。