Methylenedioxymethamphetamine inhibits mitochondrial complex I activity in mice: a possible mechanism underlying neurotoxicity. Academic Article uri icon

Overview

MeSH

  • Animals
  • Antioxidants
  • Corpus Striatum
  • Dopamine
  • Free Radicals
  • Male
  • Mice
  • Mitochondria
  • Oxidative Stress
  • Thioctic Acid

MeSH Major

  • Electron Transport Complex I
  • Hallucinogens
  • N-Methyl-3,4-methylenedioxyamphetamine
  • Neurotoxicity Syndromes

abstract

  • 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. 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. 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. 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.

publication date

  • May 2010

has subject area

  • Animals
  • Antioxidants
  • Corpus Striatum
  • Dopamine
  • Electron Transport Complex I
  • Free Radicals
  • Hallucinogens
  • Male
  • Mice
  • Mitochondria
  • N-Methyl-3,4-methylenedioxyamphetamine
  • Neurotoxicity Syndromes
  • Oxidative Stress
  • Thioctic Acid

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2874846

Digital Object Identifier (DOI)

  • 10.1111/j.1476-5381.2010.00663.x

PubMed ID

  • 20423338

Additional Document Info

start page

  • 233

end page

  • 245

volume

  • 160

number

  • 2