RESUMEN
"Ecstasy" (3,4-methylenedioxymethamphetamine or MDMA) is a widely abused recreational drug, reported to produce neurotoxic effects, both in laboratory animals and in humans. MDMA metabolites can be major contributors for MDMA neurotoxicity. This work studied the neurotoxicity of MDMA and its catechol metabolites, α-methyldopamine (α-MeDA) and N-methyl-α-methyldopamine (N-Me-α-MeDA) in human dopaminergic SH-SY5Y cells differentiated with retinoic acid and 12-O-tetradecanoyl-phorbol-13-acetate. Differentiation led to SH-SY5Y neurons with higher ability to accumulate dopamine and higher resistance towards dopamine neurotoxicity. MDMA catechol metabolites were neurotoxic to SH-SY5Y neurons, leading to caspase 3-independent cell death in a concentration- and time-dependent manner. MDMA did not show a concentration- and time-dependent death. Pre-treatment with the antioxidant and glutathione precursor, N-acetylcysteine (NAC), resulted in strong protection against the MDMA metabolites' neurotoxicity. Neither the superoxide radical scavenger, tiron, nor the inhibitor of the dopamine (DA) transporter, GBR 12909, prevented the metabolites' toxicity. Cells exposed to α-MeDA showed an increase in intracellular glutathione (GSH) levels, which, at the 48 h time-point, was not dependent in the activity increase of γ-glutamylcysteine synthetase (γ-GCS), revealing a possible transient effect. Importantly, pre-treatment with buthionine sulfoximine (BSO), an inhibitor of γ-GCS, prevented α-MeDA induced increase in GSH levels, but did not augment this metabolite cytotoxicity. Even so, BSO pre-treatment abolished NAC protective effects against α-MeDA neurotoxicity, which were, at least partially, due to GSH de novo synthesis. Inversely, pre-treatment of cells with BSO augmented N-Me-α-MeDA-induced neurotoxicity, but only slightly affected NAC neuroprotection. In conclusion, MDMA catechol metabolites promote differential toxic effects to differentiated dopaminergic human SH-SY5Y cells.
Asunto(s)
Acetilcisteína/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Síndromes de Neurotoxicidad/etiología , Sal Disódica del Ácido 1,2-Dihidroxibenceno-3,5-Disulfónico/farmacología , Butionina Sulfoximina/farmacología , Muerte Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Dipéptidos/metabolismo , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Inhibidores Enzimáticos/farmacología , Depuradores de Radicales Libres/farmacología , Glutatión/metabolismo , Humanos , Síndromes de Neurotoxicidad/patología , Piperazinas/farmacologíaRESUMEN
Seventeen months after a 1,3 million L oil spill into Guanabara Bay, analyses of mangrove sediments showed that the three sites closest to the spill remain highly polluted (>10 µg-g-1 polyaromatic hydrocarbons). A fourth site was less polluted, from which most hydrocarbon degrading bacteria were isolated.
Dezessete meses após um derramamento de 1,3 milhões de litros de óleo na Baía de Guanabara, análises de sedimento do manguezal mostraram que os três pontos de amostragem mais próximos do local do acidente permanecem altamente poluídos (>10 µg-g-1 hidrocarbonetos poliaromáticos). Do quarto ponto de amostragem, o menos poluído, foi isolada a maioria das bactérias degradadoras de hidrocarbonetos.
