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

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.

N-acetylcysteine aggravates seizures while improving depressive-like and cognitive impairment comorbidities in the WAG/Rij rat model of absence epilepsy

“…WAG/Rij rats are known to display depressive-like behaviour and cognitive impairment which are generally accepted to be strictly linked to absence seizures. In other words, it is known that their behaviour worsens with increasing seizures and is improved by treatments reducing absences [50,63,64]. This has also recently been demonstrated for the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 which dose-dependently increased absence seizures in this strain and this effect was accompanied by an increased immobility time in the FST [65]; however, some other exceptions were also previously reported [54,64,66].…”

“…In other words, it is known that their behaviour worsens with increasing seizures and is improved by treatments reducing absences [50,63,64]. This has also recently been demonstrated for the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 which dose-dependently increased absence seizures in this strain and this effect was accompanied by an increased immobility time in the FST [65]; however, some other exceptions were also previously reported [54,64,66]. Therefore, NAC may also be useful for the treatment of epilepsy comorbidities, despite an effect on seizures, at least in these patients in which seizures are not aggravated.…”

Cornerstone Cellular Pathways for Metabolic Disorders and Diabetes Mellitus: Non-Coding RNAs, Wnt Signaling, and AMPK

“…Oxidative stress occurs during the generation of ROS that can be formed by entities that include superoxide free radicals, peroxynitrite, singlet oxygen, nitric oxide, and hydrogen peroxide [80,164,[185][186][187][188][189][190][191]. With the onset of oxidative stress and the release of ROS, injury can occur to neurons [15,19,76,[191][192][193][194][195][196][197][198][199][200][201], vascular cells [33,36,38,190,[202][203][204][205][206][207], stem cells [80,199,[208][209][210], hepatic cells [51,53,[211][212][213][214][215][216], renal cells [15,43,[217]…”

“…During the presence of advanced glycation end products (AGEs) and high glucose levels with autophagy, atherosclerosis [378], cardiac disease [379], and endoplasmic reticulum stress [380] can be present. Therapy designed to improve glucose regulation with the activation of autophagy may reduce heart and liver mass [177], reduce cerebral interneuron progenitor cell survival [381], foster death of neurons [382][383][384], enhance memory loss [132,362,[385][386][387][388], and potentially injure mitochondria [46,50,178,197,220,235,343,366,[389][390][391][392]. Cellular protection with growth factors, such as EPO, requires a reduction in autophagy activation in combination with the mechanistic target of rapamycin (mTOR), protein kinase B (Akt), the proline rich Akt substrate 40 kDa (PRAS40), and mammalian forkhead transcription factors [290,306,310,340,341,[343][344][345]362,[393][394][395][396][397][398][399].…”

A Retrospective Analysis of Central and Peripheral Metabolic Characteristics in Patients with Cryptococcal Meningitis

“…Energy metabolism homeostasis is an essential requirement to maintain a biological process [ 19 , 24 ], and is regarded as a key factor affecting the prognosis of patients with CNS lesions [ 25 – 27 ]. Energy metabolism homeostasis mainly includes the metabolism of the CNS and that of the peripheral system.…”