Sustained deficiency of mitochondrial complex I activity during long periods of survival after seizures induced in immature rats by homocysteic acid |
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| Authors: | Jaroslava Folbergrová Pavel Ješina Renata Haugvicová Václav Lisý Josef Houštěk |
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| Affiliation: | 1. Institute of Chemistry, Applied Science and Technology Department, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Torino, Italy;2. Institute of Materials Physics and Engineering, Applied Science and Technology Department, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Torino, Italy;3. INSTM, Torino Politecnico Unit, Torino, Italy;4. CR-INSTM for Materials with Controlled Porosity, Italy;1. Department of Neurosciences, University of California, San Diego, CA 92037, USA;2. Departments of Medicine and Physiology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore, 117597, Singapore;3. Department of Neuroscience, University of Florida, Gainesville, FL 32611, USA;4. Department of Neurology, Soonchunhyang University Bucheon Hospital, Bucheon, 14584, Republic of Korea;5. Université de Montpellier, Montepellier, F-34095, France;6. Inserm, U 1198, Montepellier, F-34095, France;7. EPHE, Paris, F-75014, France;1. Laboratory of Physiology of Reticular Formation, National Institute of Neurology and Neurosurgery, M.V.S. Mexico, D.F., Mexico;2. Laboratory of Medical Physics, National Institute of Neurology and Neurosurgery, M.V.S. Mexico, D.F., Mexico |
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| 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 (～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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