PMID- 20423338
OWN - NLM
STAT- MEDLINE
DCOM- 20100602
LR  - 20211020
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 160
IP  - 2
DP  - 2010 May
TI  - Methylenedioxymethamphetamine inhibits mitochondrial complex I activity in mice: 
      a possible mechanism underlying neurotoxicity.
PG  - 233-45
LID - 10.1111/j.1476-5381.2010.00663.x [doi]
AB  - BACKGROUND AND PURPOSE: 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. EXPERIMENTAL 
      APPROACH: 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. KEY 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 AND IMPLICATIONS: 
      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.
FAU - Puerta, Elena
AU  - Puerta E
AD  - Department of Pharmacology, University of Navarra, Spain.
FAU - Hervias, Isabel
AU  - Hervias I
FAU - Goni-Allo, Beatriz
AU  - Goni-Allo B
FAU - Zhang, Steven F
AU  - Zhang SF
FAU - Jordan, Joaquin
AU  - Jordan J
FAU - Starkov, Anatoly A
AU  - Starkov AA
FAU - Aguirre, Norberto
AU  - Aguirre N
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Antioxidants)
RN  - 0 (Free Radicals)
RN  - 0 (Hallucinogens)
RN  - 73Y7P0K73Y (Thioctic Acid)
RN  - EC 7.1.1.2 (Electron Transport Complex I)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
CIN - Br J Pharmacol. 2010 May;160(2):217-9. PMID: 20423336
MH  - Animals
MH  - Antioxidants/pharmacology
MH  - Corpus Striatum/drug effects/metabolism
MH  - Dopamine/metabolism
MH  - Electron Transport Complex I/*antagonists & inhibitors
MH  - Free Radicals/metabolism
MH  - Hallucinogens/*toxicity
MH  - Male
MH  - Mice
MH  - Mitochondria/drug effects/metabolism
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*toxicity
MH  - Neurotoxicity Syndromes/*etiology
MH  - Oxidative Stress/drug effects
MH  - Thioctic Acid/pharmacology
PMC - PMC2874846
EDAT- 2010/04/29 06:00
MHDA- 2010/06/03 06:00
PMCR- 2011/05/01
CRDT- 2010/04/29 06:00
PHST- 2010/04/29 06:00 [entrez]
PHST- 2010/04/29 06:00 [pubmed]
PHST- 2010/06/03 06:00 [medline]
PHST- 2011/05/01 00:00 [pmc-release]
AID - BPH663 [pii]
AID - 10.1111/j.1476-5381.2010.00663.x [doi]
PST - ppublish
SO  - Br J Pharmacol. 2010 May;160(2):233-45. doi: 10.1111/j.1476-5381.2010.00663.x.