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Energy Metabolism and Redox State in Brains of Wistar Audiogenic Rats, a Genetic Model of Epilepsy

The Wistar Audiogenic Rat (WAR) strain is a genetic model of epilepsy, specifically brainstem-dependent tonic-clonic seizures, triggered by acute auditory stimulation. Chronic audiogenic seizures (audiogenic kindling) mimic temporal lobe epilepsy, with significant participation of the hippocampus, a...

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Autores principales: Dechandt, Carlos Roberto Porto, Ferrari, Gustavo Duarte, dos Santos, Jonathas Rodrigo, de Oliveira, José Antonio Cortes, da Silva-Jr, Rui Milton Patrício, Cunha, Alexandra Olimpio Siqueira, Garcia-Cairasco, Norberto, Alberici, Luciane Carla
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781615/
https://www.ncbi.nlm.nih.gov/pubmed/31632331
http://dx.doi.org/10.3389/fneur.2019.01007
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author Dechandt, Carlos Roberto Porto
Ferrari, Gustavo Duarte
dos Santos, Jonathas Rodrigo
de Oliveira, José Antonio Cortes
da Silva-Jr, Rui Milton Patrício
Cunha, Alexandra Olimpio Siqueira
Garcia-Cairasco, Norberto
Alberici, Luciane Carla
author_facet Dechandt, Carlos Roberto Porto
Ferrari, Gustavo Duarte
dos Santos, Jonathas Rodrigo
de Oliveira, José Antonio Cortes
da Silva-Jr, Rui Milton Patrício
Cunha, Alexandra Olimpio Siqueira
Garcia-Cairasco, Norberto
Alberici, Luciane Carla
author_sort Dechandt, Carlos Roberto Porto
collection PubMed
description The Wistar Audiogenic Rat (WAR) strain is a genetic model of epilepsy, specifically brainstem-dependent tonic-clonic seizures, triggered by acute auditory stimulation. Chronic audiogenic seizures (audiogenic kindling) mimic temporal lobe epilepsy, with significant participation of the hippocampus, amygdala, and cortex. The objective of the present study was to characterize the mitochondrial energy metabolism in hippocampus and cortex of WAR and verify its relationship with seizure severity. Hippocampus of WAR naïve (no seizures) presented higher oxygen consumption in respiratory states related to the maximum capacities of phosphorylation and electron transfer system, elevated mitochondrial density, lower GSH/GSSG and catalase activity, and higher protein carbonyl and lactate contents, compared with their Wistar counterparts. Audiogenic kindling had no adding functional effect in WAR, but in Wistar, it induced the same alterations observed in the audiogenic strain. In the cortex, WAR naïve presented elevated mitochondrial density, lower GSH/GSSG and catalase activity, and higher protein carbonyl levels. Chronic acoustic stimulation in Wistar induced the same alterations in cortex and hippocampus. Mainly in the hippocampus, WAR naïve presented elevated mRNA expression of glucose, lactate and excitatory amino acids transporters, several glycolytic enzymes, lactate dehydrogenase, and Na(+)/K(+) ATPase in neurons and in astrocytes. In vivo treatment with mitochondrial uncoupler 2,4-dinitrophenol (DNP) or N-acetylcysteine (NAC) in WAR had no effect on mitochondrial metabolism, but lowered oxidative stress. Unlike DNP, NAC downregulated all enzyme genes involved in glucose and lactate uptake, and metabolism in neurons and astrocytes. Additionally, it was able to reduce brainstem seizure severity in WAR. In conclusion, in WAR naïve animals, both cerebral cortex and hippocampus display elevated mitochondrial density and/or activity associated with oxidative damage, glucose and lactate metabolism pathways upregulation, and increased Na(+)/K(+) ATPase mRNA expression. Only in vivo treatment with NAC was able to reduce seizure severity of kindled WARs, possibly via down regulation of glucose/lactate metabolism. Taken together, our results are a clear contribution to the field of mitochondrial metabolism associated to epileptic seizures.
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spelling pubmed-67816152019-10-18 Energy Metabolism and Redox State in Brains of Wistar Audiogenic Rats, a Genetic Model of Epilepsy Dechandt, Carlos Roberto Porto Ferrari, Gustavo Duarte dos Santos, Jonathas Rodrigo de Oliveira, José Antonio Cortes da Silva-Jr, Rui Milton Patrício Cunha, Alexandra Olimpio Siqueira Garcia-Cairasco, Norberto Alberici, Luciane Carla Front Neurol Neurology The Wistar Audiogenic Rat (WAR) strain is a genetic model of epilepsy, specifically brainstem-dependent tonic-clonic seizures, triggered by acute auditory stimulation. Chronic audiogenic seizures (audiogenic kindling) mimic temporal lobe epilepsy, with significant participation of the hippocampus, amygdala, and cortex. The objective of the present study was to characterize the mitochondrial energy metabolism in hippocampus and cortex of WAR and verify its relationship with seizure severity. Hippocampus of WAR naïve (no seizures) presented higher oxygen consumption in respiratory states related to the maximum capacities of phosphorylation and electron transfer system, elevated mitochondrial density, lower GSH/GSSG and catalase activity, and higher protein carbonyl and lactate contents, compared with their Wistar counterparts. Audiogenic kindling had no adding functional effect in WAR, but in Wistar, it induced the same alterations observed in the audiogenic strain. In the cortex, WAR naïve presented elevated mitochondrial density, lower GSH/GSSG and catalase activity, and higher protein carbonyl levels. Chronic acoustic stimulation in Wistar induced the same alterations in cortex and hippocampus. Mainly in the hippocampus, WAR naïve presented elevated mRNA expression of glucose, lactate and excitatory amino acids transporters, several glycolytic enzymes, lactate dehydrogenase, and Na(+)/K(+) ATPase in neurons and in astrocytes. In vivo treatment with mitochondrial uncoupler 2,4-dinitrophenol (DNP) or N-acetylcysteine (NAC) in WAR had no effect on mitochondrial metabolism, but lowered oxidative stress. Unlike DNP, NAC downregulated all enzyme genes involved in glucose and lactate uptake, and metabolism in neurons and astrocytes. Additionally, it was able to reduce brainstem seizure severity in WAR. In conclusion, in WAR naïve animals, both cerebral cortex and hippocampus display elevated mitochondrial density and/or activity associated with oxidative damage, glucose and lactate metabolism pathways upregulation, and increased Na(+)/K(+) ATPase mRNA expression. Only in vivo treatment with NAC was able to reduce seizure severity of kindled WARs, possibly via down regulation of glucose/lactate metabolism. Taken together, our results are a clear contribution to the field of mitochondrial metabolism associated to epileptic seizures. Frontiers Media S.A. 2019-10-01 /pmc/articles/PMC6781615/ /pubmed/31632331 http://dx.doi.org/10.3389/fneur.2019.01007 Text en Copyright © 2019 Dechandt, Ferrari, dos Santos, de Oliveira, Silva-Jr, Cunha, Garcia-Cairasco and Alberici. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Dechandt, Carlos Roberto Porto
Ferrari, Gustavo Duarte
dos Santos, Jonathas Rodrigo
de Oliveira, José Antonio Cortes
da Silva-Jr, Rui Milton Patrício
Cunha, Alexandra Olimpio Siqueira
Garcia-Cairasco, Norberto
Alberici, Luciane Carla
Energy Metabolism and Redox State in Brains of Wistar Audiogenic Rats, a Genetic Model of Epilepsy
title Energy Metabolism and Redox State in Brains of Wistar Audiogenic Rats, a Genetic Model of Epilepsy
title_full Energy Metabolism and Redox State in Brains of Wistar Audiogenic Rats, a Genetic Model of Epilepsy
title_fullStr Energy Metabolism and Redox State in Brains of Wistar Audiogenic Rats, a Genetic Model of Epilepsy
title_full_unstemmed Energy Metabolism and Redox State in Brains of Wistar Audiogenic Rats, a Genetic Model of Epilepsy
title_short Energy Metabolism and Redox State in Brains of Wistar Audiogenic Rats, a Genetic Model of Epilepsy
title_sort energy metabolism and redox state in brains of wistar audiogenic rats, a genetic model of epilepsy
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781615/
https://www.ncbi.nlm.nih.gov/pubmed/31632331
http://dx.doi.org/10.3389/fneur.2019.01007
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