ERK-CREB-BDNF信号转导通路在抑郁症肝气郁证病理机制中的作用

Depression is one of the serious clinical diseases in the world. Among the study of nosogenesis, may include the signal transduction related to the synaptic plasticity acceptor, the regulation of the genetic transcription and the change of the gene expression of the downstream target gene. In the study we choose the ERK-CREB-BDNF signal transduction pathways as the breakthrough point, using RT-PCR and Western blot technology to probe into the relevance between hepatic depression syndrome and ERK-CREB-BDNF signal transduction pathways from center and periphery, through clinical epidemiology cross-sectional investigation and animal experiences, and reveal the nosogenesis of hepatic depression syndrome from molecular level. The study also intends to deepen and innovate liver controlling dispersion system info, provide scientific basis for the depression treatment from the depressed liver-energy dispersed, supply new treatment target to the research of new anti-depression medicine, and improve clinical depression treatment effect.

抑郁症是全球严重的临床疾病之一，发病机制中的关键可能还包括与突触可塑性相关的受体后信号转导、基因转录调控及其下游靶基因表达水平的改变。本研究拟以ERK-CREB-BDNF信号转导通路为切入点，旨在通过临床流行病学现况调查及动物实验，应用RT-PCR技术、Western blot等技术从中枢和外周探索ERK-CREB-BDNF信号转导通路与抑郁症肝气郁证的相关性，从分子水平揭示抑郁症肝气郁证的发病机制，进一步深化和创新肝主疏泄理论体系，为从疏肝论治抑郁症提供科学依据，为研发治疗抑郁症的新药提供新的治疗靶点，从而提高抑郁症的临床治疗效果。

结题摘要..研究背景.抑郁症是全球严重的临床疾病。可能与信号转导通路的改变有关。探索并部分明确与抑郁症密切相关的信号转导通路，有望为认识抑郁症发病机制及新药研发做出贡献。课题组前期研制的舒郁胶囊有较好疗效。.主要研究内容.本课题应用qPCR技术测定正常人群、抑郁症肝气郁证患者治疗前后血清中ERK、CREB、BDNFmRNA，ELISA法测定血清内BDNF；采用CMS制备抑郁症大鼠模型。采用半定量RT-PCR法检测海马、额叶ERK、 CREB、BDNFmRNA。Western-blot法检测海马及额叶ERK、CREB、BDNF蛋白表达。ELISA法检测血清BDNF。.重要结果和关键数据.1. 动物实验.1.1 RT-PCR检测各脑区基因.海马和额叶：与空白组相比模型大鼠ERK、CREB和BDNF mRNA含量降低；与模型组相比，氟西汀、舒郁组大鼠ERK、CREB和BDNF mRNA含量升高，柴胡组和白芍组大鼠CREB mRNA和BDNF mRNA含量升高。.1.2 Western blot 检测各脑区蛋白.与空白组相比模型大鼠海马和额叶p-ERK、p-CREB和BDNF表达降低；与模型组相比，氟西汀组、舒郁组大鼠海马和额叶p-ERK、P-CREB和BDNF含量升高；柴胡组大鼠海马p-ERK、p-CREB和BDNF表达降低，额叶p-ERK含量升高；白芍组大鼠海马p-ERK和BDNF表达降低。.1.3 ELISA法检测外周血BDNF表达.与空白组相比，模型组BDNF蛋白含量降低；舒郁组、氟西汀组、柴胡组及白芍组BDNF蛋白含量无显著性差异；与模型组相比，氟西汀、舒郁组、柴胡组和白芍组大鼠BDNF蛋白含量升高。.2. 临床流调.2.1 qPCR检测血清基因.与健康组相比抑郁证患者治疗前ERK、CREB和BDNF mRNA含量降低；治疗后BDNF mRNA含量升高；ERK mRNA含量升高至正常水平；CREB mRNA含量未见升高。.2.2 ELISA法检测外周血BDNF .与健康组相比抑郁症患者BDNF水平治疗前高于正常人；治疗后，BDNF有降低趋势。.科学意义.抑郁症肝气郁证的发病机制可能与海马、额叶ERK、CREB、BDNF基因及蛋白表达量下降有关。舒郁胶囊及其主要组分可通过上调上述基因及蛋白表达，改善抑郁症状。