TY - JOUR
T1 - Pro-oxidant effects of Ecstasy and its metabolites in mouse brain synaptosomes
AU - Branco, Paula Cristina de Sério
AU - Ferreira, Luísa Maria da Silva Pinto
PY - 2012/1/1
Y1 - 2012/1/1
N2 - 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, alpha-methyldopamine (alpha-MeDA), N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and 5-(glutathion-S-yl)-alpha-methyldopamine [5-(GSH)-alpha-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 alpha-MeDA, N-Me-alpha-MeDA and 5-(GSH)-alpha-MeDA, concentration- and time-dependently increased H2O2 production, 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 H2O2 generation 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.
AB - 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, alpha-methyldopamine (alpha-MeDA), N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and 5-(glutathion-S-yl)-alpha-methyldopamine [5-(GSH)-alpha-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 alpha-MeDA, N-Me-alpha-MeDA and 5-(GSH)-alpha-MeDA, concentration- and time-dependently increased H2O2 production, 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 H2O2 generation 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.
KW - synaptosomes
KW - 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy')
KW - neurotoxicity
KW - mitochondria
KW - oxidative stress
KW - monoamine oxidase
KW - MDMA metabolites
U2 - 10.1111/j.1476-5381.2011.01453.x
DO - 10.1111/j.1476-5381.2011.01453.x
M3 - Article
C2 - 21506960
SN - 0007-1188
VL - 165
SP - 1017
EP - 1033
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 4B
ER -