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Neurotoxicity of ecstasy metabolites in rat cortical neurons, and influence of hyperthermia.

Authors :
Capela, João Paulo
Meisel, Andreas
Abreu, Artur Reis
Branco, Paula Sério
Ferreira, Luísa Maria
Lobo, Ana Maria
Remião, Fernando
Bastos, Maria Lurdes
Carvalho, Félix
Source :
The Journal of Pharmacology and Experimental Therapeutics; January 2006, Vol. 316 Issue: 1 p53-61, 9p
Publication Year :
2006

Abstract

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-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 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 and also, in a minor extent, by alpha-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.

Details

Language :
English
ISSN :
00223565 and 15210103
Volume :
316
Issue :
1
Database :
Supplemental Index
Journal :
The Journal of Pharmacology and Experimental Therapeutics
Publication Type :
Periodical
Accession number :
ejs8539068
Full Text :
https://doi.org/10.1124/jpet.105.092577