Scavenging of highly reactive gamma-ketoaldehydes attenuates cognitive dysfunction associated with epileptogenesis
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-enzymati...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996116302790 |
| _version_ | 1818728779350016000 |
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| author | Jennifer N. Pearson Eric Warren Li-Ping Liang L. Jackson Roberts, II Manisha Patel |
| author_facet | Jennifer N. Pearson Eric Warren Li-Ping Liang L. Jackson Roberts, II Manisha Patel |
| author_sort | Jennifer N. Pearson |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T22:35:25Z |
| format | Article |
| id | doaj.art-7b7809f333204bfe9153813bebc72318 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T22:35:25Z |
| publishDate | 2017-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-7b7809f333204bfe9153813bebc723182022-12-21T21:30:06ZengElsevierNeurobiology of Disease1095-953X2017-02-01988899Scavenging of highly reactive gamma-ketoaldehydes attenuates cognitive dysfunction associated with epileptogenesisJennifer N. Pearson0Eric Warren1Li-Ping Liang2L. Jackson Roberts, II3Manisha Patel4Department of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, 80045, United StatesDepartment of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, 80045, United StatesDepartment of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, 80045, United StatesDivision of Clinical Pharmacology, Vanderbilt University, 37235, United States; Department of Pharmacology, Vanderbilt University, 37235, United StatesDepartment of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, 80045, United States; Corresponding author at: 12850 E. Montview Blvd V20-C238, Aurora, CO 80045, United States.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.http://www.sciencedirect.com/science/article/pii/S0969996116302790Temporal lobe epilepsyOxidative stressLearning and memoryLipid peroxidation |
| spellingShingle | Jennifer N. Pearson Eric Warren Li-Ping Liang L. Jackson Roberts, II Manisha Patel Scavenging of highly reactive gamma-ketoaldehydes attenuates cognitive dysfunction associated with epileptogenesis Neurobiology of Disease Temporal lobe epilepsy Oxidative stress Learning and memory Lipid peroxidation |
| title | Scavenging of highly reactive gamma-ketoaldehydes attenuates cognitive dysfunction associated with epileptogenesis |
| title_full | Scavenging of highly reactive gamma-ketoaldehydes attenuates cognitive dysfunction associated with epileptogenesis |
| title_fullStr | Scavenging of highly reactive gamma-ketoaldehydes attenuates cognitive dysfunction associated with epileptogenesis |
| title_full_unstemmed | Scavenging of highly reactive gamma-ketoaldehydes attenuates cognitive dysfunction associated with epileptogenesis |
| title_short | Scavenging of highly reactive gamma-ketoaldehydes attenuates cognitive dysfunction associated with epileptogenesis |
| title_sort | scavenging of highly reactive gamma ketoaldehydes attenuates cognitive dysfunction associated with epileptogenesis |
| topic | Temporal lobe epilepsy Oxidative stress Learning and memory Lipid peroxidation |
| url | http://www.sciencedirect.com/science/article/pii/S0969996116302790 |
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