Neurotoxicity of Ecstasy metabolites in rat cortical neurons, and influence of hyperthermia.
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.
Capela
João Paulo
JP
REQUIMTE, Toxicology Department, Faculty of Pharmacy, University of Porto, Rua Aníbal Cunha 164, 4099-030 Porto, Portugal. joaocapela@ff.up.pt
Meisel
Andreas
A
Abreu
Artur Reis
AR
Branco
Paula Sério
PS
Ferreira
Luísa Maria
LM
Lobo
Ana Maria
AM
Remião
Fernando
F
Bastos
Maria Lurdes
ML
Carvalho
Félix
F
D000111:Acetylcysteine / Q000494:pharmacology; D000165:Acridine Orange; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D016895:Culture Media, Serum-Free; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004996:Ethidium; D005334:Fever / Q000473:pathology*; D005456:Fluorescent Dyes; D006213:Hallucinogens / Q000378:metabolism / Q000633:toxicity*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
D016895:Culture Media, Serum-Free; D005456:Fluorescent Dyes; D006213:Hallucinogens; D004996:Ethidium; D000165:Acridine Orange; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D000111:Acetylcysteine