PRECLINICAL STUDY: Ecstasy‐induced oxidative stress to adolescent rat brain mitochondria in vivo: influence of monoamine oxidase type A

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.

Non-Serotonergic Neurotoxicity by MDMA (Ecstasy) in Neurons Derived from Mouse P19 Embryonal Carcinoma Cells

“…Clorgyline has also been shown to produce a synergistic effect on serotonin-mediated behaviour, body temperature and increased mortality in rats [9]. The inhibition of MAO-A by clorgyline did not protect rat brain mitochondria from oxidative stress produced by MDMA [9]. In our P19 neuronal model, neither of the monoamine oxidase inhibitors nor their combination had an effect on MDMA cytotoxicity confirming that monoamine oxidase was probably not involved in MDMA-induced toxicity in our model.…”

“…Pre-treatment with clorgyline, potentiated MDMA-induced increase in extracellular serotonin produced by MDMA in rat substantia nigra in vivo [69]. Clorgyline has also been shown to produce a synergistic effect on serotonin-mediated behaviour, body temperature and increased mortality in rats [9]. The inhibition of MAO-A by clorgyline did not protect rat brain mitochondria from oxidative stress produced by MDMA [9].…”

“…Metabolism of MDMA to neurotoxic metabolites [3], oxidative stress [4,5], glutamate excitotoxicity [6,7], mitochondrial dysfunction [8,9] and enhanced neurotoxicity secondary to a dose-dependent hyperthermia [10] have all been implicated. However, the main focus has been on the sympathomimetic properties of MDMA characteristic of phenylethylamine stimulants.…”

Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview

“…On the other hand, MAO-A inhibition by the specific inhibitor clorgyline (1 mg/kg, i.p.) 30 min prior to the same MDMA dose resulted in synergistic effects on 5-HT-mediated behavior and body temperature, provoking high mortality [396]. A mechanistic hypothesis has been postulated based on these findings.…”

Comparative effects of 3,4-methylenedioxymethamphetamine and 4-methylthioamphetamine on rat liver mitochondrial function

“…A great deal of research, focusing on the neurotoxic effects of MDMA to clarify the mechanism(s) underlying neurotoxicity, has reported that oxidative stress, excitotoxicity, and mitochondrial dysfunction play a major role in mediating MDMA-induced neurotoxicity (Brown and Yamamoto, 2003;Quinton and Yamamoto, 2006;Capela et al, 2007a,b;Alves et al, 2007Alves et al, , 2009). Notice has also been taken on the hepatotoxic effects of MDMA (Henry et al, 1992;Ellis et al, 1996;Andreu et al, 1998;Beitia et al, 2000).…”