Neurotoxicity of Ecstasy metabolites in rat
cortical neurons. Influence of hyperthermia
Capela JP, Meisel A, Abreu AR, Branco PS, Ferreira LM,
Lobo AM, Remiao F, Bastos ML, Carvalho F.
Faculty of Farmacy Univ. of Porto.
J Pharmacol Exp Ther. 2005 Sep 23
ABSTRACT3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy"), is a widely abused, psychoactive recreational drug. There are growing evidences that MDMA neurotoxic profile may be highly dependent on both its hepatic metabolism and body temperature. Metabolism of MDMA involves N-demethylation to 3,4-methylenedioxyamphetamine (MDA), which is also a drug of abuse. MDMA and MDA are O-demethylenated to N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and alpha-methyldopamine (alpha-MeDA), respectively, both of which are catechols that can undergo oxidation to the corresponding ortho-quinones. In the presence of glutathione (GSH), ortho-quinones may be conjugated with GSH to form glutathionyl adducts. In this study we evaluated the neurotoxicity of MDMA and of three of its metabolites, obtained by synthesis, N-Me-alpha-MeDA, alpha-MeDA and 5-(GSH)-alpha-MeDA (5-(Glutathion-S-yl)-alpha-methyldopamine) in rat cortical neuronal serum free cultures under normal (36.5 degrees C) and hyperthermic (40 degrees C) conditions. Cell viability was assessed and the mechanism of cell death was also evaluated. Our study shows that these metabolites are more neurotoxic (5-(GSH)-alpha-MeDA being the most toxic) than the parent compound MDMA. The neurotoxicity of MDMA metabolites was partially prevented by the antioxidants N-Acetylcystein (NAC) and also, in a minor extent, by alpha-phenyl-N-tert-butyl nitrone (PBN). All the tested compounds induced apoptotical cell death in cortical neurons and their neurotoxic effect was potentiated under hyperthermic conditions. These data suggests that MDMA metabolites, especially under hyperthermic conditions, contribute to MDMA-induced neurotoxicity.HHMA
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