No 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-␣-methyldopamine (N-Me-␣-MeDA) and ␣-methyldopamine (␣-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-␣-MeDA, ␣-MeDA, and 5-(GSH)-␣-MeDA [5-(glutathion-S-yl)-␣-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)-␣-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 ␣-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.

High concentrations of circulating biogenic catecholamines often exist during the course of several cardiovascular disorders. Additionally, coronary dysfunctions are prominent and frequently related to the ischemic and reperfusion phenomenon (I/R) in the heart, which leads to the release of large amounts of catecholamines, namely adrenaline, and to a sustained generation of reactive oxygen species (ROS). Thus, this work aimed to study the toxicity of adrenaline either alone or in the presence of a system capable of generating ROS [xanthine with xanthine oxidase (X/XO)], in freshly isolated, calcium tolerant cardiomyocytes from adult rats. Studies were performed for 3 h, and cardiomyocyte viability, ATP level, lipid peroxidation, protein carbonylation content, and glutathione status were evaluated, in addition to the formation of adrenaline's oxidation products and quinoproteins. Intracellular GSH levels were time-dependently depleted with no GSSG formation when cardiomyocytes were exposed to adrenaline or to adrenaline with X/XO. Meanwhile, a time-dependent increase in the rate of formation of adrenochrome and quinoproteins was observed. Additionally, as a new outcome, 5-(glutathion- S-yl)adrenaline, an adrenaline adduct of glutathione, was identified and quantified. Noteworthy is the fact that the exposure to adrenaline alone promotes a higher rate of formation of quinoproteins and glutathione adduct, while adrenochrome formation is favored where ROS production is stimulated. This study shows that the redox status of the surrounding environment greatly influences adrenaline's oxidation pathway, which may trigger cellular changes responsible for cardiotoxicity.