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Research ArticleTOXICOLOGY

Neurotoxicity of Ecstasy Metabolites in Rat Cortical Neurons, and Influence of Hyperthermia

João Paulo Capela, Andreas Meisel, Artur Reis Abreu, Paula Sério Branco, Luísa Maria Ferreira, Ana Maria Lobo, Fernando Remião, Maria Lurdes Bastos and Félix Carvalho
Journal of Pharmacology and Experimental Therapeutics January 2006, 316 (1) 53-61; DOI: https://doi.org/10.1124/jpet.105.092577
João Paulo Capela
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Andreas Meisel
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Artur Reis Abreu
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Paula Sério Branco
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Luísa Maria Ferreira
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Ana Maria Lobo
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Fernando Remião
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Maria Lurdes Bastos
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Félix Carvalho
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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-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.

Footnotes

  • This work was supported by the Hermann and Lilly Schilling Foundation and “Fundação Calouste Gulbenkian” (Ref. FCG 10/04). J.P.C. was the recipient of a Ph.D. grant from “Fundação para a Ciência e Tecnologia” (Ref. SFRD/BD/10908/2002).

  • doi:10.1124/jpet.105.092577.

  • ABBREVIATIONS: MDMA, 3,4-methylenedioxymethamphetamine (Ecstasy); 5-HT, serotonin; MDA, 3,4-methylenedioxyamphetamine; N-Me-α-MeDA, N-methyl-α-methyldopamine; α-MeDA, α-methyldopamine; ROS, reactive oxygen species; RNS, reactive nitrogen species; GSH, glutathione; 5-(GSH)-α-MeDA, 5-(glutathion-S-yl)-α-methyldopamine; NAC, N-acetylcysteine; PBS, phosphate-buffered saline; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; PBN, α-phenyl-N-tert-butyl nitrone; NAC, N-acetylcystein; DIV, day(s) in vitro.

    • Received July 14, 2005.
    • Accepted September 22, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 316 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 316, Issue 1
1 Jan 2006
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Research ArticleTOXICOLOGY

Neurotoxicity of Ecstasy Metabolites in Rat Cortical Neurons, and Influence of Hyperthermia

João Paulo Capela, Andreas Meisel, Artur Reis Abreu, Paula Sério Branco, Luísa Maria Ferreira, Ana Maria Lobo, Fernando Remião, Maria Lurdes Bastos and Félix Carvalho
Journal of Pharmacology and Experimental Therapeutics January 1, 2006, 316 (1) 53-61; DOI: https://doi.org/10.1124/jpet.105.092577

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Research ArticleTOXICOLOGY

Neurotoxicity of Ecstasy Metabolites in Rat Cortical Neurons, and Influence of Hyperthermia

João Paulo Capela, Andreas Meisel, Artur Reis Abreu, Paula Sério Branco, Luísa Maria Ferreira, Ana Maria Lobo, Fernando Remião, Maria Lurdes Bastos and Félix Carvalho
Journal of Pharmacology and Experimental Therapeutics January 1, 2006, 316 (1) 53-61; DOI: https://doi.org/10.1124/jpet.105.092577
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