NeuropharmacologyNeurotoxicity mechanisms of thioether ecstasy metabolites
Section snippets
Materials
Materials for cell cultures were obtained from the following sources: Neurobasal medium and supplement B27 from Invitrogen (Paisley, UK); Modified Eagle’s medium, phosphate buffered saline (PBS), Hepes buffer, trypsin/EDTA, penicillin/streptomycin, l-glutamine, collagen-G and poly-l-lysin from Biochrom (Berlin, Germany). 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT), nitro blue tetrazolium (NBT), potassium glycinate, phenylmethylsulfonyl fluoride (PMSF), NAC, reduced (GSH)
Thioether MDMA metabolites induced neurotoxicity in cortical neuronal cultures is concentration-, temperature- and time-dependent. Thioether MDMA metabolites are strong neurotoxins relatively to their parent catechols and MDMA
Neuronal viability assessed by the MTT test at the end of 6 h incubation period revealed toxicity for the GSH and NAC conjugates: 5-(GSH)-N-Me-α-MeDA (Fig. 1C), 5-(NAC)-N-Me-α-MeDA (Fig. 1D), 5-(GSH)-α-MeDA (Fig. 1F) and 5-(NAC)-α-MeDA (Fig. 1G). At this time-point there was a concentration-dependent-induced toxicity at both normothermia and hyperthermia for these compounds. The metabolite 5-(GSH)-N-Me-α-MeDA (Fig. 1D) showed the highest degree of neurotoxicity among the thioether MDMA
Discussion
The key findings of our study were: (1) thioether MDMA metabolites induced neurotoxicity in cortical neuronal cultures is concentration-, temperature- and time-dependent; (2) thioether MDMA metabolites are strong neurotoxins comparatively to their parent catechols and MDMA; (3) thioether MDMA metabolites induced delayed neuronal death, accompanied by activation of caspase 3; (4) thioether MDMA metabolites time-dependently induced the formation of reactive species in neurons; (5) thioether MDMA
Conclusion
In conclusion, MDMA metabolism leading to reactive thioether MDMA metabolites, which produce ROS/RNS and toxic oxidation products, has a key role in the neurotoxic events produced by “ecstasy.”
Acknowledgments
This work was supported by the “Fundação Calouste Gulbenkian” (Ref. FCG 10/04). J.P.C. was the recipient of a PhD grant from “Fundação para a Ciência e Tecnologia” (Ref. SFRD/BD/10908/2002).
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