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The Journal of Neuroscience, September 19, 2007, 27(38):10203-10210; doi:10.1523/JNEUROSCI.2645-07.2007
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Neurobiology of Disease
Monoamine Oxidase-B Mediates Ecstasy-Induced Neurotoxic Effects to Adolescent Rat Brain Mitochondria
Ema Alves,1,3 Teresa Summavielle,1,5 Cecília Juliana Alves,1 Joana Gomes-da-Silva,1,6 José Custódio Barata,7 Eduarda Fernandes,2 Maria de Lourdes Bastos,3 Maria Amélia Tavares,1,4 andFélix Carvalho3 1Neurobehaviour Unit, Instituto de Biologia Molecular e Celular, 2Physical-Chemistry Department and 3Toxicology Department, Faculty of Pharmacy, REQUIMTE, 4Institute of Anatomy, Medical School of Porto, University of Porto, 4099-002 Porto, Portugal, 5Departamento de Ciências Biomédicas, Escola Superior de Tecnologia da Saúde, Instituto Politécnico do Porto, 4000-294 Porto, Portugal, 6Escola de Saúde, University of Aveiro, 3180-193 Aveiro, Portugal, and 7Biochemistry Department, Faculty of Pharmacy, University of Coimbra, 3000-295 Coimbra, Portugal
Correspondence should be addressed to either of the following: Dr. Félix Carvalho, Toxicology Department, Faculty of Pharmacy, University of Porto, Rua Aníbal Cunha, 164, 4099-030 Porto, Portugal Email: felixdc{at}ff.up.pt; Dr. Teresa Summarielle, IBMC, Instituto de Biologia Molecular e Celular, Grupo Neurocomportamento, Rua do Campo Alegre 823, 4150-180 Porto, Portugal, Email: tsummavi{at}ibmc.up.pt
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.
Key words: 3,4-methylenedioxymethamphetamine; neurotoxicity; adolescent rat model; brain mitochondria; monoamine oxidase B; oxidative stress
Received Dec. 13, 2006; revised July 10, 2007; accepted July 16, 2007.
Correspondence should be addressed to either of the following: Dr. Félix Carvalho, Toxicology Department, Faculty of Pharmacy, University of Porto, Rua Aníbal Cunha, 164, 4099-030 Porto, Portugal Email: felixdc{at}ff.up.pt; Dr. Teresa Summarielle, IBMC, Instituto de Biologia Molecular e Celular, Grupo Neurocomportamento, Rua do Campo Alegre 823, 4150-180 Porto, Portugal, Email: tsummavi{at}ibmc.up.pt
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