TY - JOUR T1 - Neurotoxicity of Ecstasy Metabolites in Rat Cortical Neurons, and Influence of Hyperthermia JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 53 LP - 61 DO - 10.1124/jpet.105.092577 VL - 316 IS - 1 AU - João Paulo Capela AU - Andreas Meisel AU - Artur Reis Abreu AU - Paula Sério Branco AU - Luísa Maria Ferreira AU - Ana Maria Lobo AU - Fernando Remião AU - Maria Lurdes Bastos AU - Félix Carvalho Y1 - 2006/01/01 UR - http://jpet.aspetjournals.org/content/316/1/53.abstract N2 - 3,4-Methylenedioxymethamphetamine (MDMA or “Ecstasy”) is a widely abused, psychoactive recreational drug. There is growing evidence that the 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-α-methyldopamine (N-Me-α-MeDA) and α-methyldopamine (α-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 three of its metabolites obtained by synthesis, N-Me-α-MeDA, α-MeDA, and 5-(GSH)-α-MeDA [5-(glutathion-S-yl)-α-methyldopamine] in rat cortical neuronal serum-free cultures under normal (36.5°C) and hyperthermic (40°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)-α-MeDA being the most toxic] than the parent compound MDMA. The neurotoxicity of MDMA metabolites was partially prevented by the antioxidants N-acetylcystein and also, in a minor extent, by α-phenyl-N-tert-butyl nitrone. All the tested compounds induced apoptotic cell death in cortical neurons, and their neurotoxic effect was potentiated under hyperthermic conditions. These data suggest that MDMA metabolites, especially under hyperthermic conditions, contribute to MDMA-induced neurotoxicity. The American Society for Pharmacology and Experimental Therapeutics ER -