Sustained deficiency of mitochondrial complex I activity during long periods of survival after seizures induced in immature rats by homocysteic acid

Neurochem Int. 2010 Feb;56(3):394-403. doi: 10.1016/j.neuint.2009.11.011. Epub 2009 Nov 18.


Our previous work demonstrated the marked decrease of mitochondrial complex I activity in the cerebral cortex of immature rats during the acute phase of seizures induced by bilateral intracerebroventricular infusion of dl-homocysteic acid (600 nmol/side) and at short time following these seizures. The present study demonstrates that the marked decrease ( approximately 60%) of mitochondrial complex I activity persists during the long periods of survival, up to 5 weeks, following these seizures, i.e. periods corresponding to the development of spontaneous seizures (epileptogenesis) in this model of seizures. The decrease was selective for complex I and it was not associated with changes in the size of the assembled complex I or with changes in mitochondrial content of complex I. Inhibition of complex I was accompanied by a parallel, up to 5 weeks lasting significant increase (15-30%) of three independent mitochondrial markers of oxidative damage, 3-nitrotyrosine, 4-hydroxynonenal and protein carbonyls. This suggests that oxidative modification may be most likely responsible for the sustained deficiency of complex I activity although potential role of other factors cannot be excluded. Pronounced inhibition of complex I was not accompanied by impaired ATP production, apparently due to excess capacity of complex I documented by energy thresholds. The decrease of complex I activity was substantially reduced by treatment with selected free radical scavengers. It could also be attenuated by pretreatment with (S)-3,4-DCPG (an agonist for subtype 8 of group III metabotropic glutamate receptors) which had also a partial antiepileptogenic effect. It can be assumed that the persisting inhibition of complex I may lead to the enhanced production of reactive oxygen and/or nitrogen species, contributing not only to neuronal injury demonstrated in this model of seizures but also to epileptogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / metabolism
  • Animals
  • Animals, Newborn
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology
  • Cerebral Cortex / physiopathology
  • Convulsants / toxicity
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • Electron Transport Complex I / drug effects
  • Electron Transport Complex I / metabolism*
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology
  • Epilepsy / metabolism*
  • Epilepsy / physiopathology
  • Excitatory Amino Acid Agonists / pharmacology
  • Free Radical Scavengers / pharmacology
  • Homocysteine / analogs & derivatives
  • Homocysteine / toxicity
  • Male
  • Metabolic Networks and Pathways / physiology
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondrial Diseases / chemically induced
  • Mitochondrial Diseases / metabolism*
  • Mitochondrial Diseases / physiopathology
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Rats
  • Rats, Wistar
  • Seizures / chemically induced
  • Seizures / metabolism*
  • Seizures / physiopathology
  • Survival Rate
  • Time Factors
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism


  • Aldehydes
  • Convulsants
  • Excitatory Amino Acid Agonists
  • Free Radical Scavengers
  • Homocysteine
  • homocysteic acid
  • 3-nitrotyrosine
  • Tyrosine
  • Electron Transport Complex I
  • 4-hydroxy-2-nonenal