title: Mitochondrial respiration deficits driven by reactive oxygen species in experimental temporal lobe epilepsy.
abstract: Metabolic alterations have been implicated in the etiology of temporal lobe epilepsy (TLE), but whether or not they have a functional impact on cellular energy producing pathways (glycolysis and/or oxidative phosphorylation) is unknown. The goal of this study was to determine if alterations in cellular bioenergetics occur using real-time analysis of mitochondrial oxygen consumption and glycolytic rates in an animal model of TLE. We hypothesized that increased steady-state levels of reactive oxygen species (ROS) initiated by epileptogenic injury result in impaired mitochondrial respiration. We established methodology for assessment of bioenergetic parameters in isolated synaptosomes from the hippocampus of Sprague-Dawley rats at various times in the kainate (KA) model of TLE. Deficits in indices of mitochondrial respiration were observed at time points corresponding with the acute and chronic phases of epileptogenesis. We asked if mitochondrial bioenergetic dysfunction occurred as a result of increased mitochondrial ROS and if it could be attenuated in the KA model by pharmacologically scavenging ROS. Increased steady-state ROS in mice with forebrain-specific conditional deletion of manganese superoxide dismutase (Sod2(fl/fl)NEX(Cre/Cre)) in mice resulted in profound deficits in mitochondrial oxygen consumption. Pharmacological scavenging of ROS with a catalytic antioxidant restored mitochondrial respiration deficits in the KA model of TLE. Together, these results demonstrate that mitochondrial respiration deficits occur in experimental TLE and ROS mechanistically contribute to these deficits. Furthermore, this study provides novel methodology for assessing cellular metabolism during the entire time course of disease development.
authors.affiliation: Neuroscience Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Shane
authors.initials: S
authors.lastname: Rowley
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Liang
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Fulton
authors.affiliation: Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba 263-0022, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: National Jewish Health, Denver, CO 80206, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Day
authors.affiliation: Neuroscience Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: manisha.patel@ucdenver.edu.
authors.forename: Manisha
authors.initials: M
authors.lastname: Patel
mesh_terms: D000208:Acute Disease; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism*; D005260:Female; D006019:Glycolysis / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007608:Kainic Acid; D008297:Male; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D007608:Kainic Acid; D010100:Oxygen; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2
keywords: Kainic acid; Mitochondrial dysfunction; Oxidative stress; Seizures; Temporal lobe epilepsy