Pro-oxidant effects of Ecstasy and its metabolites in mouse brain synaptosomes

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BACKGROUND AND PURPOSE 3,4-Methylenedioxymethamphetamine (MDMA or Ecstasy) is a worldwide major drug of abuse known to elicit neurotoxic effects. The mechanisms underlying the neurotoxic effects of MDMA are not clear at present, but the metabolism of dopamine and 5-HT by monoamine oxidase (MAO), as well as the hepatic biotransformation of MDMA into pro-oxidant reactive metabolites is thought to contribute to its adverse effects. EXPERIMENTAL APPROACH Using mouse brain synaptosomes, we evaluated the pro-oxidant effects of MDMA and its metabolites, alpha-methyldopamine (alpha-MeDA), N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and 5-(glutathion-S-yl)-alpha-methyldopamine [5-(GSH)-alpha-MeDA], as well as those of 5-HT, dopamine, L-DOPA and 3,4-dihydroxyphenylacetic acid (DOPAC). KEY RESULTS 5-HT, dopamine, L-DOPA, DOPAC and MDMA metabolites alpha-MeDA, N-Me-alpha-MeDA and 5-(GSH)-alpha-MeDA, concentration- and time-dependently increased H2O2 production, which was significantly reduced by the antioxidants N-acetyl-L-cysteine (NAC), ascorbic acid and melatonin. From experiments with MAO inhibitors, it was observed that H2O2 generation induced by 5-HT was totally dependent on MAO-related metabolism, while for dopamine, it was a minor pathway. The MDMA metabolites, dopamine, L-DOPA and DOPAC concentration-dependently increased quinoproteins formation and, like 5-HT, altered the synaptosomal glutathione status. Finally, none of the compounds modified the number of polarized mitochondria in the synaptosomal preparations, and the compounds' pro-oxidant effects were unaffected by prior mitochondrial depolarization, excluding a significant role for mitochondrial-dependent mechanisms of toxicity in this experimental model. CONCLUSIONS AND IMPLICATIONS MDMA metabolites along with high levels of monoamine neurotransmitters can be major effectors of neurotoxicity induced by Ecstasy.
Original languageUnknown
Pages (from-to)1017-1033
JournalBritish Journal of Pharmacology
Issue number4B
Publication statusPublished - 1 Jan 2012

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