title: Scavenging of highly reactive gamma-ketoaldehydes attenuates cognitive dysfunction associated with epileptogenesis.
abstract: Cognitive dysfunction is a major comorbidity of the epilepsies; however, treatments targeting seizure-associated cognitive dysfunction, particularly deficits in learning and memory are not available. Isoketals and neuroketals, collectively known as gamma-ketoaldehydes are formed via the non-enzymatic, free radical catalyzed oxidation of arachidonic acid and docosahexaenoic acid, respectively. They are attractive candidates for oxidative protein damage and resultant cognitive dysfunction due to their formation within the plasma membrane and their high proclivity to form cytotoxic adducts on protein lysine residues. We tested the hypothesis that gamma-ketoaldehydes mechanistically contribute to seizure-associated memory impairment using a specific gamma-ketoaldehyde scavenger, salicylamine in the kainic acid and pilocarpine rat models of temporal lobe epilepsy. We show that gamma-ketoaldehydes are increased following epileptogenic injury in hippocampus and perirhinal cortex, two brain regions imperative for learning and memory. Treatment with an orally bioavailable, brain permeable scavenger, salicylamine attenuated 1) spatial memory deficits 2) reference memory deficits and 3) neuronal loss and astrogliosis in two mechanistically distinct models of epilepsy without affecting the epileptogenic injury or the development of chronic epilepsy. We have previously demonstrated that reactive oxygen species and the lipid peroxidation biomarkers, F2-isoprostanes are produced following status epilepticus. However, which reactive species specifically mediate oxidative damage to cellular macromolecules remains at large. We provide novel data suggesting that memory impairment occurs via gamma-ketoaldehyde production in two models of epilepsy and that treatment with a gamma-ketoaldehyde scavenger can protect vulnerable neurons. This work suggests a novel target and therapy to treat seizure-induced memory deficits in epilepsy.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, 80045, United States.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Pearson
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, 80045, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Warren
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, 80045, United States.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Liang
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University, 37235, United States; Department of Pharmacology, Vanderbilt University, 37235, United States.
authors.forename: L Jackson
authors.initials: LJ
authors.lastname: Roberts
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, 80045, United States. Electronic address: Manisha.Patel@ucdenver.edu.
authors.forename: Manisha
authors.initials: M
authors.lastname: Patel
mesh_terms: D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000493:pharmacokinetics / Q000494:pharmacology*; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000209:etiology / 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; D007608:Kainic Acid; D007659:Ketones / Q000378:metabolism*; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D010862:Pilocarpine; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D012458:Salicylanilides / Q000493:pharmacokinetics / Q000494:pharmacology*; D013226:Status Epilepticus / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000523:psychology
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D007659:Ketones; D018696:Neuroprotective Agents; D012458:Salicylanilides; D010862:Pilocarpine; C034596:salicylanilide; D007608:Kainic Acid
keywords: Learning and memory; Lipid peroxidation; Oxidative stress; Temporal lobe epilepsy