title: 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.
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic, vvi, Vídenská 1083, 142 20 Prague 4, Czech Republic. folbergr@biomed.cas.cz
authors.forename: Jaroslava
authors.initials: J
authors.lastname: Folbergrová
authors.forename: Pavel
authors.initials: P
authors.lastname: Jesina
authors.forename: Renata
authors.initials: R
authors.lastname: Haugvicová
authors.forename: Václav
authors.initials: V
authors.lastname: Lisý
authors.forename: Josef
authors.initials: J
authors.lastname: Houstek
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D042967:Electron Transport Complex I / Q000187:drug effects / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D004827:Epilepsy / Q000378:metabolism* / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006710:Homocysteine / Q000031:analogs & derivatives / Q000633:toxicity; D008297:Male; D053858:Metabolic Networks and Pathways / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D015996:Survival Rate; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000447:Aldehydes; D003292:Convulsants; D018690:Excitatory Amino Acid Agonists; D016166:Free Radical Scavengers; D006710:Homocysteine; C007956:homocysteic acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D042967:Electron Transport Complex I; C027576:4-hydroxy-2-nonenal