Monoamine oxidase-B mediates ecstasy-induced neurotoxic effects to adolescent rat brain mitochondria.
3,4-Methylenedioxymethamphetamine (MDMA)-induced neurotoxicity and the protective role of monoamine oxidase-B (MAO-B) inhibition were evaluated at the mitochondrial level in various regions of the adolescent rat brain. Four groups of adolescent male Wistar rats were used: (1) saline control, (2) exposed to MDMA (4 x 10 mg/kg, i.p.; two hourly), (3) treated with selegiline (2 mg/kg, i.p.) 30 min before the same dosing of MDMA, and (4) treated with selegiline (2 mg/kg, i.p.). Body temperatures were monitored throughout the whole experiment. Animals were killed 2 weeks later, and mitochondria were isolated from several brain regions. Our results showed that "binge" MDMA administration causes, along with sustained hyperthermia, long-term alterations in brain mitochondria as evidenced by increased levels of lipid peroxides and protein carbonyls. Additionally, analysis of mitochondrial DNA (mtDNA) revealed that NDI nicotinamide adenine dinucleotide phosphate dehydrogenase subunit I and NDII (nicotinamide adenine dinucleotide phosphate dehydrogenase subunit II) subunits of mitochondrial complex I and cytochrome c oxidase subunit I of complex IV suffered deletions in MDMA-exposed animals. Inhibition of MAO-B by selegiline did not reduce hyperthermia but reversed MDMA-induced effects in the oxidative stress markers, mtDNA, and related protein expression. These results indicate that monoamine oxidation by MAO-B with subsequent mitochondrial damage may be an important contributing factor for MDMA-induced neurotoxicity.
Alves
Ema
E
Neurobehaviour Unit, Instituto de Biologia Molecular e Celular, Medical School of Porto, University of Porto, 4099-002 Porto, Portugal.
Summavielle
Teresa
T
Alves
Cecília Juliana
CJ
Gomes-da-Silva
Joana
J
Barata
José Custódio
JC
Fernandes
Eduarda
E
Bastos
Maria de Lourdes
Mde L
Tavares
Maria Amélia
MA
Carvalho
Félix
F
D000367:Age Factors; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar
D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase; D018817:N-Methyl-3,4-methylenedioxyamphetamine