Abstract
The administration of a neurotoxic dose of 3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') to the rat results in mitochondrial oxidative damage in the central nervous system, namely lipid and protein oxidation and mitochondrial DNA deletions with subsequent impairment of the correspondent protein expression. Although these toxic effects were shown to be prevented by monoamine oxidase B inhibition, the role of monoamine oxidase A (MAO-A) in MDMA-mediated mitochondrial damage remains to be evaluated. Thus, the aim of the present study was to clarify the potential interference of a specific inhibition of MAO-A by clorgyline, on the deleterious effects produced by a binge administration of a neurotoxic dose of MDMA (10 mg MDMA/kg of body weight, intraperitoneally, every 2 hours in a total of four administrations) to an adolescent rat model. The parameters evaluated were mitochondrial lipid peroxidation, protein carbonylation and expression of the respiratory chain protein subunits II of reduced nicotinamide adenine dinucleotide dehydrogenase (NDII) and I of cytochrome oxidase (COXI). Considering that hyperthermia has been shown to contribute to the neurotoxic effects of MDMA, another objective of the present study was to evaluate the body temperature changes mediated by MDMA with a MAO-A selective inhibition by clorgyline. The obtained results demonstrated that the administration of a neurotoxic binge dose of MDMA to an adolescent rat model previously treated with the specific MAO-A inhibitor, clorgyline, resulted in synergistic effects on serotonin- (5-HT) mediated behaviour and body temperature, provoking high mortality. Inhibition of MAO-A by clorgyline administration had no protective effect on MDMA-induced alterations on brain mitochondria (increased lipid peroxidation, protein carbonylation and decrease in the expression of the respiratory chain subunits NDII and COXI), although it aggravated MDMA-induced decrease in the expression of COXI. These results reinforce the notion that the concomitant use of MAO-A inhibitors and MDMA is counter indicated because of the resulting severe synergic toxicity.
Highlights
The widespread consumption of 3,4-methylenedioxymethamphetamine (MDMA; ‘ecstasy’), especially among adolescents and young adults, is presently a matter of high concern because of the acute and chronic toxic effects mediated by this drug
Average values for each group are represented by horizontal bars
The results obtained in the present study demonstrate that the selective inhibition of monoamine oxidase A (MAO-A) by clorgyline has no beneficial influence on the MDMA-mediated oxidative damage in whole brain mitochondria of rats in vivo
Summary
The widespread consumption of 3,4-methylenedioxymethamphetamine (MDMA; ‘ecstasy’), especially among adolescents and young adults, is presently a matter of high concern because of the acute and chronic toxic effects mediated by this drug. Among the toxic effects mediated by MDMA, its potential to induce damage to the serotonergic nerve terminals is considered a soaring risk because of its irreversible nature. It may result in permanent neurological deficits like sleep disorders, depressed mood, persistent elevation of anxiety, impulsiveness, hostility and selective impairment of episodic memory, working memory and attention (Morgan 2000; Morton 2005). We have recently given a new insight on the neurotoxicity of MDMA by showing that, in the rat, the administration of a neurotoxic dose results in monoamine oxidase B (MAO-B)-dependent mitochondrial oxidative damage in the central nervous system (CNS), namely lipid and protein oxidation and mitochondrial DNA (mtDNA) deletion, with subsequent impairment in the corresponding protein expression (Alves et al 2007). The strong neuroprotective effect of MAO-B inhibition was independent of body temperature (Alves et al 2007)
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