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

• Type: Article in International Scientific Journal
• Date: 2012

Authors

Barbosa, J (Author) Other; Daniel Jose Barbosa (Author) Other; Joao Paulo Capela (Author) Other; Jorge M A Oliveira (Author) FFUP; Renata Silva (Author) Other; Luisa Maria Ferreira (Author) Other; Filipa Siopa (Author) Other; Paula Serio Branco (Author) Other; Eduarda Fernandes (Author) FFUP; Jose Alberto Duarte (Author) FADEUP; Maria De Lourdes Bastos (Author) FFUP; Felix Carvalho (Author) FFUP; Carvalho, D (Author) Other

Journal

Title: British Journal of Pharmacology

Vol. 165

Pages: 1017-1033

ISSN: 0007-1188

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 37 Citations

Scopus - 44 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-002-DDE

DOI: 10.1111/j.1476-5381.2011.01453.x

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 17