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

• Tipo: Artigo em Revista Científica Internacional
• Data: 2012

Autores

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

Revista

Título: British Journal of Pharmacology

Vol. 165

Páginas: 1017-1033

ISSN: 0007-1188

Editora: Wiley-Blackwell

Indexação

ISI Web of Knowledge - 37 Citações

Scopus - 44 Citações

Classificação Científica

FOS: Ciências médicas e da saúde > Medicina básica

Outras Informações

ID Authenticus: 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 17