title: Metformin Prevented Dopaminergic Neurotoxicity Induced by 3,4-Methylenedioxymethamphetamine Administration.
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.
authors.affiliation: Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Via Ospedale 72, 09124, Cagliari, Italy. p.f.porceddu@gmail.com.
authors.forename: Pier Francesca
authors.initials: PF
authors.lastname: Porceddu
authors.affiliation: Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria.
authors.forename: Ismail Ogunbayode
authors.initials: IO
authors.lastname: Ishola
authors.affiliation: Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Via Ospedale 72, 09124, Cagliari, Italy.
authors.forename: Liliana
authors.initials: L
authors.lastname: Contu
authors.affiliation: Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Via Ospedale 72, 09124, Cagliari, Italy.|CNR, Institute of Neuroscience, Cagliari, Italy.
authors.forename: Micaela
authors.initials: M
authors.lastname: Morelli
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002421:Caudate Nucleus / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011699:Putamen / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018696:Neuroprotective Agents; D008687:Metformin; D014446:Tyrosine 3-Monooxygenase; D018817:N-Methyl-3,4-methylenedioxyamphetamine
keywords: Caudate putamen; MDMA; Neurodegeneration; Neuroprotection; Substantia nigra; Tyrosine hydroxylase