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

Abstract
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.
AuthorsJaroslava Folbergrová, Pavel Jesina, Renata Haugvicová, Václav Lisý, Josef Houstek
JournalNeurochemistry international (Neurochem Int) Vol. 56 Issue 3 Pg. 394-403 (Feb 2010) ISSN: 1872-9754 [Electronic] England
PMID19931336 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright (c) 2009 Elsevier Ltd. All rights reserved.
Chemical References
  • Aldehydes
  • Convulsants
  • Excitatory Amino Acid Agonists
  • Free Radical Scavengers
  • Homocysteine
  • homocysteic acid
  • 3-nitrotyrosine
  • Tyrosine
  • Electron Transport Complex I
  • 4-hydroxy-2-nonenal
Topics
  • Aldehydes (metabolism)
  • Animals
  • Animals, Newborn
  • Cerebral Cortex (metabolism, pathology, physiopathology)
  • Convulsants (toxicity)
  • Disease Models, Animal
  • Down-Regulation (drug effects, physiology)
  • Electron Transport Complex I (drug effects, metabolism)
  • Energy Metabolism (drug effects, physiology)
  • Epilepsy (metabolism, physiopathology)
  • Excitatory Amino Acid Agonists (pharmacology)
  • Free Radical Scavengers (pharmacology)
  • Homocysteine (analogs & derivatives, toxicity)
  • Male
  • Metabolic Networks and Pathways (physiology)
  • Mitochondria (drug effects, metabolism)
  • Mitochondrial Diseases (chemically induced, metabolism, physiopathology)
  • Oxidative Stress (drug effects, physiology)
  • Rats
  • Rats, Wistar
  • Seizures (chemically induced, metabolism, physiopathology)
  • Survival Rate
  • Time Factors
  • Tyrosine (analogs & derivatives, metabolism)

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