GLP-1通过上调大脑AMPK/PGC1α通路降低2型糖尿病并发帕金森病风险的机制研究

Type 2 diabetes (T2D) increases risk of Parkinson's disease (PD). Meanwhile, glucagon-like peptide-1 (GLP-1) mimetics, a type of anti-diabetic drugs, has been proved to be effective in reducing dopaminergic neuron loss, but the mechanism is unclear. Previous studies implicated that T2D and PD might be linked by mitochondrial dysfunction. AMPK/PGC1α pathway is an important pathway in regulating mitochondrial function, while GLP-1 can activate AMPK directly. And our previous work found that in striatum of glucose intolerant rats, the DA level decreased, and AMPK activation was down regulated. Thus, we hypothesize that in T2D, GLP-1 mimetics can improve mitochondrial function via up-regulating AMPK/PGC1α pathway, and then alleviate dopaminergic neuron damage, and decrease risk of PD. This project will determine the effect of EX-4, a GLP-1 receptor agonist, on AMPK/PGC1α pathways, and on the early pathophysiologic changes of PD in T2D mice. Meanwhile, we will also study the effect of EX-4 on primary dopaminergic neurons under high glucose, insulin resistant, or toxin environment, and the related mechanism. The aim of this project is to explore the mechanism underlying the protective effect of GLP-1 mimetics on dopaminergic neurons, and to provide a solid theoretical foundation for the application of GLP-1 mimetics in preventing T2D patients progressing into PD, or in treating patients with both T2D and PD.

2型糖尿病（T2D）可显著增加帕金森病（PD）的发病风险。GLP-1类药物作为T2D的治疗药物，在PD中亦有减轻多巴胺神经元损伤的作用，但机制未明。研究发现，多巴胺神经元损伤多由线粒体功能异常引起，且后者是T2D和PD发病的共同改变。AMPK/PGC1α是调控线粒体功能的重要通路，而GLP-1可直接激活AMPK。申请者亦发现，糖耐量受损大鼠纹状体内多巴胺含量下降，AMPK活性下调。据此推测：T2D时GLP-1类药物可通过上调脑内AMPK/PGC1α通路，改善线粒体功能，减轻多巴胺神经元损伤，降低PD风险。本项目拟考察T2D小鼠模型中，GLP-1受体激动剂EX-4对AMPK/PGC1α信号通路、PD早期病理生理改变的影响；并研究在高糖、胰岛素抵抗、以及毒物环境下，EX-4对原代多巴胺神经元的保护作用及机制。本课题旨在阐明GLP-1类药物保护多巴胺神经元的机制，为其应用于T2D合并PD的防治提供理论基础。

越来越多的证据提示2型糖尿病（T2D）与帕金森病（PD）存在联系。GLP-1类药物作为T2D的治疗药物，在PD中亦有减轻多巴胺神经元损伤的作用，但机制未明。本项目采用T2D小鼠模型db/db小鼠，分别观察了GLP-1受体激动剂对幼年以及成年db/db小鼠黑质-纹状体系统中AMPK/PGC1α信号通路以及PD早期病理生理改变的影响；并研究了在高糖及毒物等多种应激环境下，GLP-1受体激动剂对多巴胺神经元细胞模型的保护作用及机制。结果显示：在幼年db/db小鼠中预防性的应用GLP-1类药物可以减轻多巴胺神经元的损伤，并且改善AMPK/PGC1a信号通路；而在已发病的成年db/db小鼠中长期给予GLP-1类药物干预可以延缓db/db小鼠行为学障碍的进展，亦可减轻多巴胺神经元的损伤，并且改善AMPK/PGC1a信号通路。在SH-SY5Y细胞中开展的实验进一步证实了AMPK信号通路在GLP-1类药物的神经保护作用中起着关键作用。