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

The international journal of neuropsychopharmacology, 2016-09, Vol.19 (9), p.pyw047 [Peer Reviewed Journal]

The Author 2016. Published by Oxford University Press on behalf of CINP. 2016 ;The Author 2016. Published by Oxford University Press on behalf of CINP. ;ISSN: 1461-1457 ;EISSN: 1469-5111 ;DOI: 10.1093/ijnp/pyw047 ;PMID: 27207919

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  • Title:
    Metformin Prevents Dopaminergic Neuron Death in MPTP/P-Induced Mouse Model of Parkinson’s Disease via Autophagy and Mitochondrial ROS Clearance
  • Author: Lu, Ming ; Su, Cunjin ; Qiao, Chen ; Bian, Yaqi ; Ding, Jianhua ; Hu, Gang
  • Is Part Of: The international journal of neuropsychopharmacology, 2016-09, Vol.19 (9), p.pyw047
  • Description: 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.
  • Publisher: US: Oxford University Press
  • Language: English
  • Identifier: ISSN: 1461-1457
    EISSN: 1469-5111
    DOI: 10.1093/ijnp/pyw047
    PMID: 27207919
  • Source: PubMed Central
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    Oxford Academic Journals (Open Access)
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