Metformin protects rotenone-induced dopaminergic neurodegeneration by reducing lipid peroxidation
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Metformin protects rotenone‑induced dopaminergic neurodegeneration by reducing lipid peroxidation Gul Ozbey1 · Dilara Nemutlu‑Samur1 · Hande Parlak2 · Sendegul Yildirim3 · Mutay Aslan4 · Gamze Tanriover3 · Aysel Agar2 Received: 24 July 2019 / Revised: 21 November 2019 / Accepted: 9 January 2020 © Maj Institute of Pharmacology Polish Academy of Sciences 2020
Abstract Background Metformin, a widely prescribed antidiabetic drug, has been suggested to have a neuroprotective effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in mice. In this study, we investigated the neuroprotective potential of metformin against rotenone-induced dopaminergic neuron damage and its underlying mechanisms. Methods C57BL/6 mice were given saline or rotenone (2.5 mg/kg/day, ip) injection for 10 days. Metformin treatment (300 mg/kg/day, ip) was started concurrently with rotenone administration and continued for 10 days. The neuroprotective effect of metformin on rotenone-induced dopaminergic toxicity was assessed by tyrosine hydroxylase (TH), cleaved caspase-3 and α-synuclein immunohistochemistry in substantia nigra (SN). SN tissues were extracted for biochemical analysis. Malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) protein levels were measured by spectrophotometric assay. Results We found that metformin treatment attenuated the rotenone-induced loss of TH+ neurons in the SN. Additionally, metformin significantly decreased the rotenone-induced increase of cleaved caspase-3 and α-synuclein accumulation in the SN; however, there was no difference in motor behaviours between the experimental groups. Meanwhile, the levels of MDA and 4-HNE in SN were significantly reduced in the rotenone-metformin group compared to the rotenone group. Conclusions Results showed that metformin treatment attenuated dopaminergic neuron loss in SN induced by rotenone by decreasing lipid peroxidation. Keywords Parkinson’s disease · Metformin · Rotenone · Lipid peroxidation
Introduction Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder and is characterized by cardinal motor symptoms that do not manifest until the dopaminergic neuron degeneration reaches to at least 50% in SNpc [1, 2]. Although the underlying mechanisms of PD * Gul Ozbey [email protected] 1
Department of Pharmacology, Akdeniz University Medical Faculty, Dumlupinar Street, 07070 Antalya, Turkey
2
Department of Physiology, Akdeniz University Medical Faculty, Dumlupinar Street, 07070 Antalya, Turkey
3
Department of Histology and Embryology, Akdeniz University Medical Faculty, Dumlupinar Street, 07070 Antalya, Turkey
4
Department of Biochemistry, Akdeniz University Medical Faculty, Dumlupinar Street, 07070 Antalya, Turkey
are still under debate, mitochondrial dysfunction, oxidative stress, neuroinflammation and aggregation of alpha-synuclein (α-synuclein) as toxic oligomers in Lewy bodies seem to overlap the pathways in the progressive death of dopaminergic neurons [3]. Rotenone, which
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