The mixture of "ecstasy" and its metabolites is toxic to human SH-SY5Y differentiated cells at in vivo relevant concentrations

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Daniel Jose Barbosa (Author) Other; Joao Paulo Capela (Author) Other; Renata Silva (Author) Other; Vania Vilas Boas (Author) Other; Luisa Maria Ferreira (Author) Other; Paula Serio Branco (Author) Other; Eduarda Fernandes (Author) FFUP; Maria de Lourdes Bastos (Author) FFUP; Felix Carvalho (Author) FFUP

Journal

Title: Archives of Toxicology

Vol. 88

Pages: 455-473

ISSN: 0340-5761

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 24 Citations

Scopus - 35 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-009-5GN

DOI: 10.1007/s00204-013-1120-7

Abstract (EN): The neurotoxicity of "ecstasy" (3,4-methylenedioxymethamphetamine, MDMA) is thought to involve hepatic metabolism, though its real contribution is not completely understood. Most in vitro neurotoxicity studies concern isolated exposures of MDMA or its metabolites, at high concentrations, not considering their mixture, as expected in vivo. Therefore, our postulate is that combined deleterious effects of MDMA and its metabolites, at low micromolar concentrations that may be attained into the brain, may elicit neurotoxicity. Using human SH-SY5Y differentiated cells as dopaminergic neuronal model, we studied the neurotoxicity of MDMA and its MDMA metabolites alpha-methyldopamine and N-methyl-alpha-methyldopamine and their correspondent glutathione and N-acetylcysteine monoconjugates, under isolated exposure and as a mixture, at normothermic or hyperthermic conditions. The results showed that the mixture of MDMA and its metabolites was toxic to SH-SY5Y differentiated cells, an effect potentiated by hyperthermia and prevented by N-acetylcysteine. As a mixture, MDMA and its metabolites presented a different toxicity profile, compared to each compound alone, even at equimolar concentrations. Caspase 3 activation, increased reactive oxygen species production, and intracellular Ca2+ raises were implicated in the toxic effect. The mixture increased intracellular glutathione levels by increasing its de novo synthesis. In conclusion, this study demonstrated, for the first time, that the mixture of MDMA and its metabolites, at low micromolar concentrations, which represents a more realistic approach of the in vivo scenario, elicited toxicity to human SH-SY5Y differentiated cells, thus constituting a new insight into the context of MDMA-related neurotoxicity.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 19