电针治疗抑郁症快速起效的分子通路机制研究

The initiating agent of depression is the excitement of the HPA axis induced by stimulus. One of the final results was the apoptosis of the cerebral neurons, and the upriver signal passage with the participation of the CREB-BDNF was the critical link of this process. Based on the previous researches funded by National Natural Science Foundation of China,electroacupuncture showed anti-depressive effect by regulating CREB-BDNF, and this might explain the mechanism that why electroacupuncture take effect earlier than Fluoxetine. In this study, we combine the clinical trial and experimental study with the objects of depression patients and chronic-mild-stress-induced depression model rats. Behavior analysis and molecular biological techniques are used for outcome measurements and Fluoxetine is used as control treatment method. The purpose of this research is to probe into the key targets of the signal passages of the upper reaches of CREB (including cAMP signal passage and CaMK signal passage), and illuminate the mechanism of electroacupuncture by investigating the relations and net system between the signal passages and the key targets, and then provide evidence for the coordination of drugs and acupuncture treatment and the optimization of treatment protocols. This would be helpful for improving the science evidence and therapeutic efficacy for depression in clinical practice.

抑郁症的始动因素是机体受到刺激导致HPA轴兴奋，其结果之一是脑部神经细胞的萎缩凋亡，而环磷腺苷反应元件结合蛋白(CREB)参与的上游信号转导通路是上述致病过程的关键环节。基于前期国家自然基金等多项基金的资助，发现电针可以调节CREB-脑源性神经营养因子（BDNF）环节治疗抑郁症，而且较氟西汀起效快速，这可能与电针调控多靶点协同起效的机制相关。本项目结合基础与临床试验，拟以抑郁症患者和慢性应激性抑郁症模型大鼠为研究对象，以氟西汀为对照，参照行为学和分子生物学相关指标，着眼于CREB上游两条主要信号通路（cAMP通路和CaMK通路）的关键靶点，探讨电针参与该信号通路、关键靶点及相关的神经递质和受体之间的关系，构建其间相互关联的网络体系，阐明电针快速起效的分子机制,为探索电针与药物协同作用、优化电针抗抑郁方案提供科学依据,对抑郁症的治疗方法及疗效的改进和提高有重要的科学意义和临床实用价值。

课题组前期研究表明，电针法对抑郁症临床疗效确切，明显优于西药，有起效快、低复发、无不良反应的优势。本项目在前期研究的基础上，结合基础与临床试验，以抑郁症患者和慢性应激性抑郁症模型大鼠为研究对象，以氟西汀为对照，参照行为学和分子生物学相关指标，着眼于CREB上游主要信号通路的关键靶点，以及miRNAs转录后调控水平，探讨电针治疗的不同时期调控相应信号通路、关键靶点及相关的神经递质和受体之间的关系，阐明了电针快速起效的分子机制。研究发现电针治疗抑郁症起效时间早于氟西汀，其原因可能是电针在治疗早期即可通过调节Glu和GABA水平及相关信号通路改善模型大鼠抑郁症躯体症状，同时激活BDNF/TrkB/CREB信号通路，增强神经营养；转录后调控水平研究结果显示，电针在治疗早期可通过调节相关miRNAs水平，调控GABAergic synapse、Dopaminergic synapse及PI3K-Akt signaling pathway等信号通路。这些信号通路的激活一方面能够显著改善抑郁症躯体症状，同时能够在电针治疗中后期协同激活神经营养和神经递质相关通路，进一步加强加快电针治疗抑郁症的疗效。本研究为探索电针与药物协同作用、优化电针抗抑郁方案提供科学依据,对抑郁症的治疗方法及疗效的改进和提高有重要的科学意义和临床实用价值。