Bayliss Jacqueline A, Lemus Moyra B, Santos Vanessa V, Deo Minh, Davies Jeffrey S, Kemp Bruce E, Elsworth John D, Andrews Zane B
Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Clayton, Melbourne, Vic., 3800, Australia.
Molecular Neurobiology, Institute of Life Science, Swansea University, Swansea, SA28PP, United Kingdom.
PLoS One. 2016 Jul 28;11(7):e0159381. doi: 10.1371/journal.pone.0159381. eCollection 2016.
Metformin is a widely prescribed drug used to treat type-2 diabetes, although recent studies show it has wide ranging effects to treat other diseases. Animal and retrospective human studies indicate that Metformin treatment is neuroprotective in Parkinson's Disease (PD), although the neuroprotective mechanism is unknown, numerous studies suggest the beneficial effects on glucose homeostasis may be through AMPK activation. In this study we tested whether or not AMPK activation in dopamine neurons was required for the neuroprotective effects of Metformin in PD. We generated transgenic mice in which AMPK activity in dopamine neurons was ablated by removing AMPK beta 1 and beta 2 subunits from dopamine transporter expressing neurons. These AMPK WT and KO mice were then chronically exposed to Metformin in the drinking water then exposed to MPTP, the mouse model of PD. Chronic Metformin treatment significantly attenuated the MPTP-induced loss of Tyrosine Hydroxylase (TH) neuronal number and volume and TH protein concentration in the nigrostriatal pathway. Additionally, Metformin treatment prevented the MPTP-induced elevation of the DOPAC:DA ratio regardless of genotype. Metformin also prevented MPTP induced gliosis in the Substantia Nigra. These neuroprotective actions were independent of genotype and occurred in both AMPK WT and AMPK KO mice. Overall, our studies suggest that Metformin's neuroprotective effects are not due to AMPK activation in dopaminergic neurons and that more research is required to determine how metformin acts to restrict the development of PD.
二甲双胍是一种广泛应用于治疗2型糖尿病的药物，尽管最近的研究表明它对治疗其他疾病也有广泛的作用。动物研究和回顾性人体研究表明，二甲双胍治疗对帕金森病（PD）具有神经保护作用，尽管其神经保护机制尚不清楚，但大量研究表明，其对葡萄糖稳态的有益作用可能是通过激活AMPK实现的。在本研究中，我们测试了多巴胺能神经元中AMPK的激活是否是二甲双胍对PD神经保护作用所必需的。我们构建了转基因小鼠，通过从表达多巴胺转运体的神经元中去除AMPKβ1和β2亚基，消除多巴胺能神经元中的AMPK活性。然后，将这些AMPK野生型和敲除型小鼠长期饮用含二甲双胍的水，随后暴露于MPTP（PD的小鼠模型）。长期使用二甲双胍治疗可显著减轻MPTP诱导的黑质纹状体通路中酪氨酸羟化酶（TH）神经元数量、体积及TH蛋白浓度的损失。此外，无论基因型如何，二甲双胍治疗均可防止MPTP诱导的DOPAC:DA比值升高。二甲双胍还可预防MPTP诱导的黑质胶质细胞增生。这些神经保护作用与基因型无关，在AMPK野生型和AMPK敲除型小鼠中均有发生。总体而言，我们的研究表明，二甲双胍的神经保护作用并非由于多巴胺能神经元中AMPK的激活，需要更多的研究来确定二甲双胍如何发挥作用以限制PD的发展。
