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 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.
Highlights
Epilepsy is one of the most common diseases involving the central nervous system [1]
Wistar and Wistar audiogenic rat (WAR) were submitted to chronic stimulation and the seizure behaviors were categorized according to Rossetti et al [8]
Biopsies from WAR group presented higher oxygen consumption compared to Wistar rats in almost all respiratory states: NADH-linked and in respiratory states related to the maximum capacities of phosphorylation and electron transfer system, such as OXPHOS, and non-coupled
Summary
Epilepsy is one of the most common diseases involving the central nervous system [1]. Since the 1920s, studies have demonstrated that the ketogenic diet may be antiepileptogenic, suggesting an altered energy metabolism of neurons of patients with epilepsy. Some side effects of the ketogenic diet include certain mitochondrial cytopathies such as Complex I and carnitine deficiencies [for a review [2]], suggesting that mitochondrial energy metabolism plays a central role in the pathology and therapeutics of epilepsy, a complex mechanism yet to be unraveled. In order to study brain networks participation in the expression of epileptic seizures, animal models of epilepsy have been developed, among them the Wistar audiogenic rat (WAR) strain was developed from inbreeding of Wistar susceptible progenitors [3,4,5]. There is no description of mitochondrial energy metabolism in WAR’s brains
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