Acetyl-L-carnitine provides effective in vivo neuroprotection over 3,4-methylenedioximethamphetamine-induced mitochondrial neurotoxicity in the adolescent rat brain.
3,4-Methylenedioximethamphetamine (MDMA, ecstasy) is a worldwide abused stimulant drug, with persistent neurotoxic effects and high prevalence among adolescents. The massive release of 5-HT from pre-synaptic storage vesicles induced by MDMA followed by monoamine oxidase B (MAO-B) metabolism, significantly increases oxidative stress at the mitochondrial level. l-Carnitine and its ester, acetyl-l-carnitine (ALC), facilitate the transport of long chain free fatty acids across the mitochondrial membrane enhancing neuronal anti-oxidative defense. Here, we show the potential of ALC against the neurotoxic effects of MDMA exposure. Adolescent male Wistar rats were assigned to four groups: control saline solution, isovolumetric to the MDMA solution, administered i.p.; MDMA (4x10 mg/kg MDMA, i.p.); ALC/MDMA (100 mg/kg 30 min of ALC prior to MDMA, i.p.) and ALC (100 mg/kg, i.p.). Rats were killed 2 weeks after exposure and brains were analyzed for lipid peroxidation, carbonyl formation, mitochondrial DNA (mtDNA) deletion and altered expression of the DNA-encoded subunits of the mitochondrial complexes I (NADH dehydrogenase, NDII) and IV (cytochrome c oxidase, COXI) from the respiratory chain. Levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were also assessed. The present work is the first to successfully demonstrate that pretreatment with ALC exerts effective neuroprotection against the MDMA-induced neurotoxicity at the mitochondrial level, reducing carbonyl formation, decreasing mtDNA deletion, improving the expression of the respiratory chain components and preventing the decrease of 5-HT levels in several regions of the rat brain. These results indicate potential benefits of ALC application in the prevention and treatment of neurodegenerative disorders.
Alves
E
E
IBMC-Instituto de Biologia Molecular e Celular, Molecular Neurobiology, Neuroprotection Laboratory, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal.
Binienda
Z
Z
Carvalho
F
F
Alves
C J
CJ
Fernandes
E
E
de Lourdes Bastos
M
M
Tavares
M A
MA
Summavielle
T
T
D000108:Acetylcarnitine / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000473:pathology / Q000648:ultrastructure; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D005334:Fever / Q000139:chemically induced; D006213:Hallucinogens / Q000633:toxicity*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D028361:Mitochondrial Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009245:NADH Dehydrogenase / Q000378:metabolism; D050050:Protein Carbonylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D014803:Vitamin B Complex / Q000627:therapeutic use*
D004272:DNA, Mitochondrial; D006213:Hallucinogens; D008565:Membrane Proteins; D014803:Vitamin B Complex; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D000108:Acetylcarnitine; D051545:Cyclooxygenase 1; C496513:Ptgs1 protein, rat; D009245:NADH Dehydrogenase; D018817:N-Methyl-3,4-methylenedioxyamphetamine