Methylenedioxymethamphetamine inhibits mitochondrial complex I activity in mice: a possible mechanism underlying neurotoxicity.
OBJECTIVE
3,4-methylenedioxymethamphetamine (MDMA) causes a persistent loss of dopaminergic cell bodies in the substantia nigra of mice. Current evidence indicates that such neurotoxicity is due to oxidative stress but the source of free radicals remains unknown. Inhibition of mitochondrial electron transport chain complexes by MDMA was assessed as a possible source.


METHODS
Activities of mitochondrial complexes after MDMA were evaluated spectrophotometrically. In situ visualization of superoxide production in the striatum was assessed by ethidium fluorescence and striatal dopamine levels were determined by HPLC as an index of dopaminergic toxicity.


RESULTS
3,4-methylenedioxymethamphetamine decreased mitochondrial complex I activity in the striatum of mice, an effect accompanied by an increased production of superoxide radicals and the inhibition of endogenous aconitase. alpha-Lipoic acid prevented superoxide generation and long-term toxicity independent of any effect on complex I inhibition. These effects of alpha-lipoic acid were also associated with a significant increase of striatal glutathione levels. The relevance of glutathione was supported by reducing striatal glutathione content with L-buthionine-(S,R)-sulfoximine, which exacerbated MDMA-induced dopamine deficits, effects suppressed by alpha-lipoic acid. The nitric oxide synthase inhibitor, N(G)-nitro-L-arginine, partially prevented MDMA-induced dopamine depletions, an effect reversed by L-arginine but not D-arginine. Finally, a direct relationship between mitochondrial complex I inhibition and long-term dopamine depletions was found in animals treated with MDMA in combination with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.


CONCLUSIONS
Inhibition of mitochondrial complex I following MDMA could be the source of free radicals responsible for oxidative stress and the consequent neurotoxicity of this drug in mice.
Puerta
Elena
E
Department of Pharmacology, University of Navarra, Spain.
Hervias
Isabel
I
Goñi-Allo
Beatriz
B
Zhang
Steven F
SF
Jordán
Joaquín
J
Starkov
Anatoly A
AA
Aguirre
Norberto
N
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D005609:Free Radicals / Q000378:metabolism; D006213:Hallucinogens / Q000633:toxicity*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D018384:Oxidative Stress / Q000187:drug effects; D008063:Thioctic Acid / Q000494:pharmacology
D000975:Antioxidants; D005609:Free Radicals; D006213:Hallucinogens; D008063:Thioctic Acid; D042967:Electron Transport Complex I; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine