title: Reactive oxygen species mediate cognitive deficits in experimental temporal lobe epilepsy.
abstract: Cognitive dysfunction is an important comorbidity of temporal lobe epilepsy (TLE). However, no targeted therapies are available and the mechanisms underlying cognitive impairment, specifically deficits in learning and memory associated with TLE remain unknown. Oxidative stress is known to occur in the pathogenesis of TLE but its functional role remains to be determined. Here, we demonstrate that oxidative stress and resultant processes contribute to cognitive decline associated with epileptogenesis. Using a synthetic catalytic antioxidant, we show that pharmacological removal of reactive oxygen species (ROS) prevents 1) oxidative stress, 2) deficits in mitochondrial oxygen consumption rates, 3) hippocampal neuronal loss and 4) cognitive dysfunction without altering the intensity of the initial status epilepticus (SE) or epilepsy development in a rat model of SE-induced TLE. Moreover, the effects of the catalytic antioxidant on cognition persisted beyond the treatment period suggestive of disease-modification. The data implicate oxidative stress as a novel mechanism by which cognitive dysfunction can arise during epileptogenesis and suggest a potential disease-modifying therapeutic approach to target it.
authors.affiliation: Neuroscience Program, University of Colorado, Anschutz Medical Campus, 80045, USA.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Pearson
authors.affiliation: Neuroscience Program, University of Colorado, Anschutz Medical Campus, 80045, USA.
authors.forename: Shane
authors.initials: S
authors.lastname: Rowley
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, 80045, USA.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Liang
authors.affiliation: Department of Pediatrics, University of Colorado, Anschutz Medical Campus, 80045, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: White
authors.affiliation: National Jewish Health, Denver, CO 80206, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Day
authors.affiliation: Neuroscience Program, University of Colorado, Anschutz Medical Campus, 80045, USA; Department of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, 80045, USA. Electronic address: Manisha.Patel@ucdenver.edu.
authors.forename: Manisha
authors.initials: M
authors.lastname: Patel
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000523:psychology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018697:Nootropic Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010862:Pilocarpine; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013226:Status Epilepticus / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000523:psychology
chemical_list: D000975:Antioxidants; D018697:Nootropic Agents; D017382:Reactive Oxygen Species; D010862:Pilocarpine
keywords: Epilepsy; Learning and memory; Mitochondrial dysfunction; Neuronal loss; Oxidative stress; Pilocarpine; Reactive oxygen species