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.
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Authors | Jaroslava Folbergrová, Pavel Jesina, Renata Haugvicová, Václav Lisý, Josef Houstek |
Journal | Neurochemistry international
(Neurochem Int)
Vol. 56
Issue 3
Pg. 394-403
(Feb 2010)
ISSN: 1872-9754 [Electronic] England |
PMID | 19931336
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright (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
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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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