Metformin Prevents Dopaminergic Neuron Death in MPTP/P-Induced Mouse Model of Parkinson's Disease via Autophagy and Mitochondrial ROS Clearance

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.