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

Abstract

Background: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.Methods: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.Results: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.Conclusions: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.

Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging

“…Another recent study has also shown that metformin, an MTORC1 inhibitor currently used to treat type 2 diabetes, may activate autophagy flux in the SN of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTPp) mouse model of PD. Metformin attenuates inflammasome activation and pro-inflammatory cytokine TNF-α and IL-6 levels while increasing anti-inflammatory IL-10 levels [161], suggesting that autophagy may control the SN inflammatory response in an in vivo model of PD. However, this report did not provide evidence of the specific role of microglia on MPTPp elicited PD-like inflammatory response.…”

ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition

“…In SH-SY5Y cells, metformin effectively suppressed cell proliferation, invasion potential, and sphere-forming ability [21,22]. On the contrary, metformin attenuated the cytotoxicity induced by 1-methyl-4-phenylpyridinium (MPP + ) [23] or α-synuclein [24] in SH-SY5Y cells. Interestingly, it was reported that lowering the glucose level potentiated metformin-induced cytotoxicity in breast cancer cells [25].…”

Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson’s Disease

“…Each of these effects was prevented by the AMPK inhibitor compound C and by the macroautophagy inhibitor 3-Methyladenine (3-MA). These findings suggest that AMPK activation via metformin is neuroprotective through multiple mechanisms, including decreased neuroinflammation, clearance of αSyn, and increased mitochondrial quality control [170]. Similar results were observed in mice treated with MPTP for 1 week followed by 1 week of metformin treatment [171].…”

“…Metformin is the most widely prescribed medication for type-2 diabetes (T2D) and has well-established effects in the liver but is also taken up in the brain [169]. Treatment of mice with metformin for 5 weeks significantly ameliorated MPTP-induced degeneration of SNc DA neurons, partially restored striatal DA content, and fully restored normal motor behavior on the rotarod test [170]. Metformin also increased macroautophagy, reduced αSyn, decreased reactive microglia, and attenuated expression of proinflammatory cytokines.…”