BACKGROUND AND PURPOSE: 3,4‐Methylenedioxymethamphetamine (MDMA or ‘Ecstasy’) is a worldwide major drug of abuse known to elicit neurotoxic effects. The mechanisms underlying the neurotoxic effects of MDMA are not clear at present, but the metabolism of dopamine and 5‐HT by monoamine oxidase (MAO), as well as the hepatic biotransformation of MDMA into pro‐oxidant reactive metabolites is thought to contribute to its adverse effects.EXPERIMENTAL APPROACH: Using mouse brain synaptosomes, we evaluated the pro‐oxidant effects of MDMA and its metabolites, α‐methyldopamine (α‐MeDA), N‐methyl‐α‐methyldopamine (N‐Me‐α‐MeDA) and 5‐(glutathion‐S‐yl)‐α‐methyldopamine [5‐(GSH)‐α‐MeDA], as well as those of 5‐HT, dopamine,l‐DOPA and 3,4‐dihydroxyphenylacetic acid (DOPAC).KEY RESULTS: 5‐HT, dopamine,l‐DOPA, DOPAC and MDMA metabolites α‐MeDA, N‐Me‐α‐MeDA and 5‐(GSH)‐α‐MeDA, concentration‐ and time‐dependently increased H₂O₂production, which was significantly reduced by the antioxidants N‐acetyl‐l‐cysteine (NAC), ascorbic acid and melatonin. From experiments with MAO inhibitors, it was observed that H₂O₂generation induced by 5‐HT was totally dependent on MAO‐related metabolism, while for dopamine, it was a minor pathway. The MDMA metabolites, dopamine,l‐DOPA and DOPAC concentration‐dependently increased quinoproteins formation and, like 5‐HT, altered the synaptosomal glutathione status. Finally, none of the compounds modified the number of polarized mitochondria in the synaptosomal preparations, and the compounds’ pro‐oxidant effects were unaffected by prior mitochondrial depolarization, excluding a significant role for mitochondrial‐dependent mechanisms of toxicity in this experimental model.CONCLUSIONS AND IMPLICATIONS: MDMA metabolites along with high levels of monoamine neurotransmitters can be major effectors of neurotoxicity induced by Ecstasy.

Understanding the mechanisms of toxicity of ionic liquids at the molecular level is crucial for their conscious design as to promote higher acceptability as green solvents in a wide range of applications. In this systematic study, we investigated the effects of three families of ionic liquids on the plasma membrane of the filamentous fungus Aspergillus nidulans. Using fluorescence microscopy and gene expression analysis, we were able to demonstrate that the widely studied 1-alkyl-3-methylimidazolium chlorides with long alkyl substituents cause membrane permeabilisation. In opposition, the biocompatibility of cholinium alkanoates was reinforced here, even though their toxicity also increases with the elongation of the anion. Further investigating the effects of charge on membrane permeabilisation, we observed that a series of alkyl-(2-hydroxyethyl)-dimethylammonium bromides led to permeabilisation of the fungal plasma membrane by increasing the length of one alkyl substituent in the cholinium cation. We hypothesise that the chemical nature of the plasma membrane, which presents a heterogeneous charge distribution along its surface, is pivotal for the membrane permeabilising effects of ionic liquids. This study may inspire a new trend in the ionic liquid field: to give preference for the development of compounds carrying functionalised anions as greener alternatives to those carrying functionalized cations.