温胆汤调控BDNF/TrKB/CREB信号传导通路对精神分裂症认知障碍的防治作用及机制研究

In the study of the basic theory of traditional Chinese medicine(TCM), qi stagnation and phlegm coagulation is a potential pathogenesis of schizophrenia and the treatment of the schizophrenia mostly starts with the “ sputum ”. Wendan Decoction(WDD) is always used to treat the schizophrenia which is causing by the TCM intangible of phlegm and its curative effect is widely affirmed in clinical. Cognitive disorder is widely existed in schizophrenics patients, which seriously affects their quality of life and social function. BDNF/ TrkB/ CREB singalling pathway in the hippocampus plays an important role in the maintaining the function of schizophrenia cognition. BDNF also plays an important role in the parts of synaptic plasticity, long-term potentiation as well as learning and memorizing by binding to the TrkB receptors. What is more, the expression of the BDNF is directly regulate by the CREB. On the basis of previous research , this project explored the effect of WDD which can prevent and treat the cognitive impairment in schizophrenia from the molecular level of cells and the the overall level of animals, studying its regulation effect of BDNF/ TrkB/ CREB singalling pathway in the hippocampus and its downstream key material, observing the HT22 gene and CREB gene knockout HT22 cells and the change of  molecule expression such as BDNF, TrkB, CREB, Akt, ERK, Syn1 and Syp in the hippocampus. It is hoped that through this study, the signalling pathway can be found to be a potential target for psychotropic drug therapy and to develop effective compound drugs for the treatment of cognitive impairment in schizophrenia.

中医认为气滞痰凝是精神分裂症潜在病机，治疗多从“痰”入手。温胆汤临床多用治疗“无形之痰”所致精神疾患，疗效得到肯定。认知障碍广泛存在于精神分裂症患者，严重影响患者的生活质量和社会功能。海马BDNF/TrKB/CREB信号传导通路在精神分裂症认知功能维持中起重要作用，BDNF通过与TrkB受体结合在神经突触可塑性、长时程增强及学习记忆方面扮演着极其重要角色，而BDNF的表达直接受到CREB的调节。本项目在前期研究基础上从细胞分子水平和动物整体水平探讨温胆汤对精神分裂症认知障碍的防治作用，研究其对海马BDNF/TrkB/CREB 信号通路及其下游通路关键物质的调控作用，观察HT22和CREB基因敲除HT22细胞及海马组织中BDNF、TrkB、CREB、Akt、ERK、Syn1、Syp等分子表达变化，希望通过此研究发现精神药物治疗的潜在靶点，研制出有效的治疗精神分裂症认知障碍的复方中药。

精神分裂症的临床治疗从最初关注阳性症状和阴性症状的缓解，逐渐扩展到认知功能障碍的改善、社会功能恢复、生活质量的提高上，认知功能的恢复在精神分裂症的治疗中有着非常重要意义。经典抗精神病药物对治疗精神分裂症的阳性症状及阴性症状具有较好的疗效，但对认知障碍疗效不佳，且可以引起锥体外系的不良反应。因此，开展有效的中药和新疗法的系列研究是非常有必要的。.精神分裂症患者中医辨证分型多属痰湿内阻型，以沉默痴呆、语无伦次、静而多郁为特征，其临床症状与谷氨酸功能低下引起的精神分裂症的阴性症状相似。中医认为气滞痰凝是精神分裂症潜在病机，治疗多从“痰”入手。温胆汤临床多用治疗“无形之痰”所致精神疾患，疗效得到肯定。.海马BDNF/TrKB/CREB信号传导通路在精神分裂症认知功能维持中起重要作用，BDNF通过与其特异性受体TrkB结合在神经突触可塑性、长时程增强及学习记忆方面扮演着极其重要角色，而BDNF的表达直接受到CREB的调节。总之，BDNF/TrkB/CREB信号分子参与了神经元发育、突触连接和长时程增强形成，调节突触蛋白合成，也是成熟的神经元维持生存及正常生理功能所必需的分子。.本项目在前期研究基础上从细胞分子水平和动物整体水平探讨了温胆汤对精神分裂症认知障碍的防治作用，研究其对海马BDNF/TrkB/CREB 信号通路及其下游通路关键物质的调控作用，观察HT22和CREB基因沉默HT22细胞及海马组织中BDNF、TrkB、CREB、Akt、ERK、Syn1、Syp等分子表达变化。通过实验研究，发现温胆汤能够通过改善精神分裂症模型鼠的刻板行为和共济失调，增加前额叶皮层神经递质的释放，上调额叶和海马BDNF/TrkB/CREB信号通路关键分子的表达水平，减轻皮层神经元的病理损伤，从而达到改善模型鼠精神分裂样症状并提高其学习、记忆等认知功能。