bFGF促进神经细胞分化及神经递质分泌治疗帕金森病的作用研究

Parkinson’s Disease (PD) is one of the most common neurodegenerative disorder. It is characterized by a marked loss of dopaminergic neurons of mainly the substantia nigra (SN) pars compacta leading to a reduction of dopamine (DA) in the target structure, the striatum. There is no cure for Parkinson's disease，the administration of Levodopa can temporarily diminish the motor symptoms. Basic fibroblast growth factor (bFGF) is a physiological relevant neurotrophic factor in the nigrostriatal system. It promotes survival and neurite outgrowth of DA neurons and protects them from neurotoxin-induced death, also induces proliferation, differentiation and migration of neural stem cells, and hence a promising candidate for the establishment of alternative therapeutic strategies in neurodegenerative disorder. Our initial experiments showed that bFGF can initiate differentiation of neural stem cells in vitro, also increase DA content in PD animal brain. Based on these, in this project, we’ll observe the relief of PD symptoms through analysis of the animal behavior and striatal dopamine content, and investigate the effects of bFGF administration on dopaminergic neurons that differentiated from neural stem cells and the neurotransmitter changes related enzymes and proteins. By analyzing the difference between the different groups in vitro and in vivo to make clear the related gene expression and signal pathway in the process of neural stem cells differentiation through the effect of bFGF administration. We’ll explore a possible mechanism of bFGF action for treating PD. These expected results would be valuable for the design of new drugs for PD treatment and the development of new therapeutic strategies in PD through protection and substitution of mesencephalic dopaminergic neurons.

帕金森病(PD)是一种易发于中老年人的神经系统变性疾病，主要病理改变是黑质多巴胺（DA）能神经元变性，纹状体内DA含量减少。碱性成纤维细胞生长因子（bFGF）是近年来引起关注的神经营养因子,能保护神经元，诱导神经干细胞增殖、分化及迁移，在神经系统疾病治疗方面潜在着的临床价值。我们前期的实验表明，bFGF能使体外培养的神经干细胞分化DA能神经元，同时也使PD动物模型脑中DA含量升高。本项目拟通过动物行为学观察bFGF对PD症状的改善状况，利用原代培养神经干细胞分析给药前后大鼠不同脑区神经干细胞定向分化成DA能神经元的情况，电化学方法和代谢组学方法检测脑中神经递质变化情况；对比不同细胞和动物组别之间的差异，明确bFGF影响神经干细胞诱导分化过程中相关基因的表达和可能的信号传递途径，初步阐明bFGF影响PD神经递质通路和神经元分化治疗PD的机制。本项目将为帕金森病的发病机制及治疗提供新的思路。

帕金森病（PD）是一种好发于中老年人的中枢神经退行性疾病，主要病理特征是黑质-纹状体内多巴胺（DA）能神经元的变性，导致脑部神经递质DA缺乏。碱性成纤维细胞生长因子（bFGF）在神经系统疾病的治疗方面具有潜在的临床价值。本研究证实bFGF能通过激活PI3K/Akt和ERK1/2通路，引起内质网应激和抑制α-Syn蛋白过表达，促进酪氨酸羟化酶（TH）的表达，增加神经递质的合成，从而实现对PD的神经保护作用。通过1H NMR代谢组学方法，我们证实bFGF可改善PD模型大鼠脑纹状体中氨基酸类神经递质异常代谢，使损伤的DA神经元逐渐恢复正常的有氧呼吸。我们发现PD脑中一些代谢异常的氨基酸类小分子，如乳酸、γ-氨基丁酸、谷氨酸、肌酸、甘氨酸和肌醇含量异常增加，而N-乙酰天门冬氨酸、牛磺酸的含量明显减少。而且，同属一个亚家族的aFGF通过降低TRB3表达，激活自噬，降低DA能神经元凋亡，改善PD症状。本研究为PD发病机制、发展演化以及治疗研究提供新的研究方法和思路。