Th17/Treg调节炎症反应与卒中后抑郁的机制研究

Post-stroke depression is a serious complication of stroke patients. Inflammatory reaction and inhibit inflammation present throughout the physiological stage of recovery after stroke. Helper T cell (Th 17) and regulatory T cells (Treg) play the dual effect on the regulation of inflammation and directly affect a variety of complications or not. Th17/Treg closely associated with the occurrence of depression. BDNF and its related genes involved in hypoxia response to the central nervous system. That is probably one of the molecular mechanisms of depression after stroke to this process. In this study, one year follow-up study will be performed in patients with of stroke. The relationships among brain function, neurological function, the numbers of Th17/Treg and inflammatory cytokines will be analyzed, and were compared between patients with depression after stroke or not. That aimed to confirm that Th17/Treg is involved in the regulation of the inflammatory response and the occurrence of depression after stroke. Then the rat model of post-stroke depression will be established, and the behavioral characteristics, inflammation, brain morphology, and status BDNF gene pathway of rats were analyzed. The dynamic changes in the process of stress depression formed in the post-infarction will be investigated to discuss the role and status of Th17/Treg in the process of post-stroke depression. The molecular mechanisms is preliminary analyzed, it may provide the basis for elucidating biological mechanisms of post-stroke depression.

卒中后抑郁是脑卒中患者严重的并发症，卒中后炎症反应和抑制炎症贯穿卒中后恢复的整个生理阶段，辅助性T细胞17（Th17）和调控性T细胞（Treg）对炎症双重效应起调控作用，直接影响了多种并发症的发生与否。Th17/Treg与抑郁的发生关系密切。BDNF及其相关的基因参与中枢神经系统缺氧应答，可能是卒中后到抑郁发生这一过程的子机制之一。本研究对脑卒中患者进行一年随访研究，分析患者脑功能、神经功能、Th17/Treg数量、炎症因子之间的关联，比较发生卒中后抑郁和不发生患者之间的区别，确认卒中后Th17/Treg参与调控的炎症反应与抑郁发生有关。建立大鼠卒中后抑郁模型，分析大鼠行为特征、炎症状态、脑形态以及BDNF通路基因的状况，并动态比较其在梗死后至应激形成抑郁过程中的变化，了解Th17/Treg在卒中后抑郁发生过程中的确切作用和地位，初步分析分子机制，为阐明卒中后抑郁发生的生物学机制提供依据。

卒中后抑郁是卒中后患者出现情绪低落、兴趣下降和睡眠障碍等特征，并且可影响患者的认知功能以及原发疾病的康复和转归。目前卒中后抑郁的发病机制尚不明确。阐明卒中后抑郁的发病机制是当今科学研究的重要命题之一。本项目主要研究内容是围绕PSD的发病机制而展开的。该项目一方面成功建立大脑中动脉栓塞术后合并慢性温和不可预知性刺激制备卒中后抑郁大鼠（PSD）模型方法，结果发现：1）PSD大鼠外周血Treg 阳性细胞数显著低于正常组；2）PSD大鼠海马区，尤其是CA2区ARNT2蛋白表达异常升高，海马区TrkB、CREB、PSD-95 的蛋白表达明显降低；3）抗抑郁药物舍曲林处理可逆转PSD诱导的海马区 TrkB、CREB、PSD-95 蛋白下调。一方面，重复经颅磁（rTMS）处理可逆转抑郁大鼠所致的神经元凋亡，改善抑郁症状。在本资金的资助下，临床水平进一步证实，卒中恢复期Th17/Treg比值失衡与患者抑郁发作密切有关；急性脑梗死患者MRI影像学分析结果扣带回，海马旁回，额中回FA值下降与抑郁的发生呈相关性；5-HTT的基因多态性可能与PSD发病因素有关；PSD患者外周血炎症因子和NPAS4的表达与非PSD患者有显著差异；急性脑梗死患者的血清 IL-18 含量、社会支持度等方面可能在急性缺血性卒中患者抑郁发生中起重要作用；PSD患者给予舍曲林联合塞来昔布治疗取得较好疗效；在常规干预基础上辅以RT治疗，可进一步改善PSD患者睡眠障碍及HRV。该项目进一步阐明了PSD发病机制，揭示了rTMS在治疗抑郁症方面的价值；发现PSD患者在认知功能、基因水平、功能影像学等方面有明显的改变，药物治疗、RT治疗等治疗方式的有效性，可以为PSD患者的诊断、鉴别诊断及治疗方面提供一定的科学依据。