Metformin Prevents Dopaminergic Neuron Death in MPTP/P-Induced Mouse Model of Parkinson's Disease via Autophagy and Mitochondrial ROS Clearance
Metformin Prevents Dopaminergic Neuron Death in MPTP/P-Induced Mouse Model of Parkinson's Disease via Autophagy and Mitochondrial ROS Clearance
复制标题
二甲双胍通过自噬和线粒体 ROS 清除防止 MPTP/P 诱导的帕金森病小鼠模型中的多巴胺能神经元死亡
DOI：
10.1093/ijnp/pyw047
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发表时间：
2016-09-01
影响因子：
4.8
通讯作者：
Hu, Gang
中科院分区：
文献类型：
--
作者：
Lu, Ming;Su, Cunjin;Hu, Gang
我们以前的研究表明，代谢性炎症加剧了2型糖尿病小鼠多巴胺能神经元的变性。二甲双胍是一种典型的口服降糖药，被认为是AMP激活的蛋白激酶的激活剂和全身能量代谢的调节剂。本研究采用1-甲基-4-苯基-1，2，3，6-四氢吡啶加丙磺舒诱导的帕金森病小鼠模型，探讨二甲双胍对黑质多巴胺能神经元的保护作用。我们接下来培养SH-SY 5 Y细胞以研究二甲双胍的神经保护作用的机制。我们发现，二甲双胍（5 mg/mL在饮用水中）治疗5周显著改善黑质多巴胺能神经元的变性，增加纹状体多巴胺能水平，并改善1-甲基-4-苯基-1，2，3，6-四氢吡啶加丙磺舒诱导的运动障碍。我们进一步发现，二甲双胍抑制了1-甲基-4-苯基-1，2，3，6-四氢吡啶加丙磺舒帕金森病小鼠黑质中小胶质细胞过度激活诱导的神经炎症，这可能有助于二甲双胍对神经变性的保护作用。此外，二甲双胍（2 mM）激活SH-SY 5 Y细胞中的AMP活化蛋白激酶，进而诱导微管相关蛋白1轻链3-II介导的自噬并消除线粒体活性氧。因此，二甲双胍减轻MPP+诱导的细胞毒性和衰减neuronal apoptosis.我们的研究结果表明，二甲双胍可能是一个多能和有前途的药物多巴胺能神经元变性，这将使我们深入了解二甲双胍的潜力，在开辟新的治疗途径帕金森病。
Our previous study demonstrated that metabolic inflammation exacerbates dopaminergic neuronal degeneration in type 2 diabetes mice. Metformin, a typical oral hypoglycemic agent for diabetes, has been regarded as an activator of AMP-activated protein kinase and a regulator of systemic energy metabolism. Although metformin plays potential protective effects in many disorders, it is unclear whether metformin has a therapeutic role in dopaminergic neuron degeneration in Parkinson's disease.In the present study, a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus probenecid-induced mouse model of Parkinson's disease was established to explore the neuroprotective effect of metformin on dopaminergic neurons in substania nigra compacta. We next cultured SH-SY5Y cells to investigate the mechanisms for the neuroprotective effect of metformin.We showed that treatment with metformin (5mg/mL in drinking water) for 5 weeks significantly ameliorated the degeneration of substania nigra compacta dopaminergic neurons, increased striatal dopaminergic levels, and improved motor impairment induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus probenecid. We further found that metformin inhibited microglia overactivation-induced neuroinflammation in substania nigra compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus probenecid Parkinson's disease mice, which might contribute to the protective effect of metformin on neurodegeneration. Furthermore, metformin (2mM) activated AMP-activated protein kinase in SH-SY5Y cells, in turn inducing microtubule-associated protein 1 light chain 3-II-mediated autophagy and eliminating mitochondrial reactive oxygen species. Consequently, metformin alleviated MPP+-induced cytotoxicity and attenuated neuronal apoptosis.Our findings demonstrate that metformin may be a pluripotent and promising drug for dopaminergic neuron degeneration, which will give us insight into the potential of metformin in terms of opening up novel therapeutic avenues for Parkinson's disease.