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Metformin Prevented Dopaminergic Neurotoxicity Induced by 3,4-Methylenedioxymethamphetamine Administration

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Abstract

Metformin, a well-known antidiabetic drug, has recently been proposed to promote neurogenesis and to have a neuroprotective effect on the neurodegenerative processes induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in models of Parkinson’s disease. Interestingly, metformin has antioxidant properties and is involved in regulating the production of cytokines released during the neuroinflammatory process. Several studies have reported that 3,4-methylenedioxymethamphetamine (MDMA), a recreational drug mostly consumed by young adults, produces a persistent loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and caudate putamen (CPu) of mice. The aim of this study was to investigate the potential neuroprotective effect of metformin against short- and long-term neurotoxicity induced by MDMA and its role on MDMA-induced hyperthermia. Adult mice received metformin (2 × 200 mg/kg, 11-h intervals, administered orally), MDMA (4 × 20 mg/kg, 2-h interval, administered intraperitoneally), or MDMA plus metformin (2 × 200 mg/kg, 1 h before the first MDMA administration and 4 h after the last). On the second and third day, mice were treated with vehicle or metformin (1 × 200 mg/kg) and sacrificed 48 h and 7 days after the last MDMA administration. The neuroprotective effect of metformin on MDMA-induced dopaminergic damage was evaluated by dopamine transporter (DAT) and tyrosine hydroxylase (TH) immunohistochemistry in SNc and CPu. Metformin prevented the MDMA-induced loss of TH-positive neurons in the SNc and TH- and DAT-positive fibers in CPu, both at 48 h and 7 days after the last MDMA administration. These results show that metformin is neuroprotective against the short- and long-lasting dopaminergic neurodegeneration induced by MDMA.

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Acknowledgments

The authors appreciate the IBRO-ARC short stay grant award to Dr. Ishola IO. This study was supported by funds from Regione Autonoma della Sardegna (Legge Regionale 7 Agosto 2007, N.7, annualità 2010). Dr. Pier Francesca Porceddu gratefully acknowledges the Sardinian Regional Government for financial support (Legge Regionale 7 Agosto 2007, N.7, annualità 2010). Dr. Liliana Contu gratefully acknowledges the University of Cagliari for the financial support (D.R. n. 269 2014). The authors are grateful to prof. Antonio Plumitallo for the synthesis of MDMA.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Via Ospedale 72, 09124, Cagliari, Italy

    Pier Francesca Porceddu, Liliana Contu & Micaela Morelli

  2. Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria

    Ismail Ogunbayode Ishola

  3. CNR, Institute of Neuroscience, Cagliari, Italy

    Micaela Morelli

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  1. Pier Francesca Porceddu
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  2. Ismail Ogunbayode Ishola
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  3. Liliana Contu
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  4. Micaela Morelli
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Correspondence to Pier Francesca Porceddu.

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Porceddu, P.F., Ishola, I.O., Contu, L. et al. Metformin Prevented Dopaminergic Neurotoxicity Induced by 3,4-Methylenedioxymethamphetamine Administration. Neurotox Res 30, 101–109 (2016). https://doi.org/10.1007/s12640-016-9633-5

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