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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
Porto Dechandt, Carlos Roberto [1] ; Ferrari, Gustavo Duarte [1] ; dos Santos, Jonathas Rodrigo [1] ; Cortes de Oliveira, Jose Antonio [2] ; Patricio Silva-Jr, Rui Milton ; Siqueira Cunha, Alexandra Olimpio [3] ; Garcia-Cairasco, Norberto [3] ; Alberici, Luciane Carla [1]
Total Authors: 8
Affiliation:
[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Fis & Quim, Ribeirao Preto - Brazil
[2] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Fisiol, Ribeirao Preto - Brazil
[3] Patricio Silva-Jr, Jr., Rui Milton, Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Fisiol, Ribeirao Preto - Brazil
Total Affiliations: 3
Document type: Journal article
Source: FRONTIERS IN NEUROLOGY; v. 10, OCT 1 2019.
Web of Science Citations: 0
Abstract

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 naive (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 naive 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 naive 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 naive 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. (AU)

FAPESP's process: 14/03989-6 - Uncovering pathophysiological and molecular mechanisms involved in tumorigenesis by platforms for next-generation sequencing (NGS)
Grantee:Margaret de Castro
Support type: Research Projects - Thematic Grants
FAPESP's process: 18/10089-2 - Neural, hormonal and nutritional control of autophagy
Grantee:Isis Do Carmo Kettelhut
Support type: Research Projects - Thematic Grants
FAPESP's process: 16/23509-4 - Identification of neuroprotective myokines released by human skeletal muscle at low and high intensity contractions: role of mitochondrial bioenergetics and oxidative stress
Grantee:Luciane Carla Alberici
Support type: Regular Research Grants
FAPESP's process: 15/22327-7 - Analysis of electrophysiological and morphofunctional properties of neurons in the central nucleus of inferior colliculus related to genesis and spreading of sound-induced convulsive seizures
Grantee:Alexandra Olimpio Siqueira Cunha
Support type: Research Grants - Young Investigators Grants
FAPESP's process: 19/00849-2 - Uncovering pathophysiological and molecular mechanisms involvedin tumorigenesis by platforms for next-generation sequencing (NGS)
Grantee:Rui Milton Patrício da Silva Junior
Support type: Scholarships in Brazil - Post-Doctorate