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Metformin lowers α-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson's disease

Katila, Nikita, Bhurtel, Sunil, Shadfar, Sina, Srivastav, Sunil, Neupane, Sabita, Ojha, Uttam, Jeong, Gil-Saeng, Choi, Dong-Young·2017·Neuropharmacology
DOI 10.1016/j.neuropharm.2017.08.015
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Abstract

In spite of the massive research for the identification of neurorestorative or neuroprotective intervention for curing Parkinson's disease (PD), there is still lack of clinically proven neuroprotective agents. Metformin, a common anti-hyperglycemic drug has been known to possess neuroprotective properties. However, specific mechanisms by which metformin protects neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity remain to be elucidated. In this study, we assessed the neuroprotective effects of metformin in the subchronic MPTP model of PD, and explored its feasible mechanisms for neuroprotection. Animals received saline or MPTP injection (30 mg/kg/day) for the first 7 days, and then saline or metformin (200 mg/kg/day) for the next 7 days. Immunohistochemical stainings showed that metformin rescued the tyrosine hydroxylase-positive neurons and attenuated astroglial activation in the nigrostriatal pathway. In parallel, metformin restored dopamine depletion and behavioral impairments exerted by MPTP. Western blot analysis revealed that metformin ameliorated MPTP-induced α-synuclein phosphorylation which was accompanied by increased methylation of protein phosphatase 2A (PP2A), a phosphatase related to α-synuclein dephosphorylation. Moreover, the metformin regimen significantly increased the level of brain derived neurotrophic factor in the substantia nigra, and activated signaling pathways related to cell survival. Proof of concept study revealed that…

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  • Metformin induces nuclear retention of AUF1, disrupting its interaction with target mRNAs, and is neuroprotective in different Parkinson's disease models in part by decreasing SNCA levels, phosphorylation, and aggregation.

    “Coincidentally, the hypoglycemic agent metformin that induces nuclear retention of AUF1 disrupting its interaction with target mRNAs [31], is neuroprotective in different PD models in part by decreasing SNCA levels [32], phosphorylation [33,34] and aggregation [35].”

    From RNA binding protein AUF1/HNRNPD regulates nuclear export, stability and translation of SNCA transcripts (2023) · cites this paper as [33]

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Metadata

Authors
Katila, N., Bhurtel, S., Shadfar, S., Srivastav, S., Neupane, S., Ojha, U., Jeong, G.-S., & Choi, D.-Y.
Venue
Neuropharmacology
Publisher
Elsevier BV
Published
2017-10
Volume
125
Pages
396-407
ISSN
0028-3908
DOI
10.1016/j.neuropharm.2017.08.015
Cited by
169
References
6
Language
en
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Funders
  • Korea Foundation
  • Korean Government

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