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.

Metabolic Dysfunction and Oxidative Stress in Epilepsy

“…Animal models of acquired epilepsy have shown seizure-induced oxidative damage to vulnerable mitochondrial and hippocampal proteins (complex I and aconitase, etc. ), mitochondrial DNA (8-OhdG), and various lipids in the hippocampus, the site of characteristic and selective seizure-induced neurodegeneration at times preceding overt neuronal death [ 10 , 11 , 14 , 84 , 85 , 86 , 87 ]. In epilepsy, key mediators of neuronal death are necrosis initiated by glutamate excitotoxicity and apoptosis [ 88 , 89 , 90 , 91 , 92 , 93 ].…”

“…Neuronal death, particularly in the hippocampus, is a common feature of acquired epilepsy and is thought to contribute to cognitive dysfunction [ 107 ]. Importantly, attenuation of oxidative damage in models of acquired epilepsy appears to protect against cognitive dysfunction as well as confer neuroprotection [ 85 , 105 , 106 ]. Thus, oxidative damage results from seizure activity in acquired epilepsy and appears to contribute to seizure-induced neuronal loss and cognitive dysfunction.…”

Pharmacological targeting of brain inflammation in epilepsy: Therapeutic perspectives from experimental and clinical studies

“…20,113,115,116 Oxidative stress contributes to epilepsy-associated neuropathology and behavioral deficits, and plays a role in determining seizure threshold in animal models. 113,[117][118][119][120][121] Recent evidence gives support for a disease-modification effect mediated by antioxidant treatments, namely the investigational compound 1400W 122 or the combination of clinically-used drugs (i.e., N-acetylcysteine [NAC] and sulforaphane [SFN]). 20 The therapeutic effects of the antioxidant drug combination were associated with the prevention of disulfide HMGB1 generation.…”

Reactive Carbonyl Species Scavengers—Novel Therapeutic Approaches for Chronic Diseases

“…Continuous treatment with 2-HOBA in humanized ApoE4 (hApoE4) mice, a model of Alzheimer’s disease, beginning at 3 months of age significantly inhibited memory loss that is normally seen at 12–14 months of age in these mice [138]. 2-HOBA also reduced IsoLG adducts and protected against memory loss in two mouse models of epilepsy [139]. …”

“…Efficacy in animals models of Alzheimer’s disease [138], epilepsy [139], aging [140], and hypertension [39, 40]…”