Selective hyperactivation of JNK2 in an animal model of temporal lobe epilepsy
c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family and are derived from three genes, Jnk1-3. These kinases are involved in cellular responses to homeostatic insults, such as inflammation and apoptosis. Furthermore, increased JNK expression and activatio...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-06-01
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| Series: | IBRO Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2451830120300029 |
| _version_ | 1817985068760563712 |
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| author | A.N. Parikh F.A. Concepcion M.N. Khan R.D. Boehm O.C. Poolos A. Dhami N.P. Poolos |
| author_facet | A.N. Parikh F.A. Concepcion M.N. Khan R.D. Boehm O.C. Poolos A. Dhami N.P. Poolos |
| author_sort | A.N. Parikh |
| collection | DOAJ |
| description | c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family and are derived from three genes, Jnk1-3. These kinases are involved in cellular responses to homeostatic insults, such as inflammation and apoptosis. Furthermore, increased JNK expression and activation are associated with debilitating neurodegenerative diseases, including Alzheimer’s and Parkinson’s. We previously reported elevated levels of phosphorylated JNK (pJNK), indicative of JNK hyperactivation, in the CA1 hippocampus of chronically epileptic rats. We also showed that pharmacological inhibition of JNK activity reduced seizure frequency in a dose-dependent fashion (Tai TY et al., Neuroscience, 2017). Building on these observations, the objectives of this current study were to investigate the timeline of JNK activation during epileptogenesis, and to identify the JNK isoform(s) that undergo hyperactivation in the chronic epilepsy stage. Western blotting analysis of CA1 hippocampal homogenates showed JNK hyperactivation only during the chronic phase of epilepsy (6–9 weeks post-status epilepticus), and not in earlier stages of epileptogenesis (1 h, 1 day, and 1 week post-status epilepticus). After enrichment for pJNK by immunoprecipitation, we identified JNK2 as the only significantly hyperactivated JNK isoform, with expression of the 54 kDa pJNK2 variant elevated to a greater extent than the 46 kDa pJNK2 variant. Expression of the total amounts of both JNK2 variants (phosphorylated plus non-phosphorylated) was reduced in epilepsy, however, suggesting that activation of upstream phosphorylation pathways was responsible for JNK2 hyperactivation. Since our prior work demonstrated that pharmacological inhibition of JNK activation had an antiepileptic effect, JNK2 hyperactivation is therefore likely a pathological event that promotes seizure occurrences. This investigation provides evidence that JNK2 is selectively hyperactivated in epilepsy and thus may be a novel and selective antiepileptic target. |
| first_indexed | 2024-04-13T23:53:29Z |
| format | Article |
| id | doaj.art-369e3a44dd0f498c8369248cb7f4971a |
| institution | Directory Open Access Journal |
| issn | 2451-8301 |
| language | English |
| last_indexed | 2024-04-13T23:53:29Z |
| publishDate | 2020-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | IBRO Reports |
| spelling | doaj.art-369e3a44dd0f498c8369248cb7f4971a2022-12-22T02:24:00ZengElsevierIBRO Reports2451-83012020-06-0184855Selective hyperactivation of JNK2 in an animal model of temporal lobe epilepsyA.N. Parikh0F.A. Concepcion1M.N. Khan2R.D. Boehm3O.C. Poolos4A. Dhami5N.P. Poolos6Department of Neurology and Regional Epilepsy Center, University of Washington, Seattle, WA, United StatesDepartment of Neurology and Regional Epilepsy Center, University of Washington, Seattle, WA, United StatesDepartment of Neurology and Regional Epilepsy Center, University of Washington, Seattle, WA, United StatesDepartment of Neurology and Regional Epilepsy Center, University of Washington, Seattle, WA, United StatesDepartment of Neurology and Regional Epilepsy Center, University of Washington, Seattle, WA, United StatesDepartment of Neurology and Regional Epilepsy Center, University of Washington, Seattle, WA, United StatesCorresponding author at: Department of Neurology and Regional Epilepsy Center, Box 356465, 1959 NE Pacific Way, Seattle, WA, 98195, United States.; Department of Neurology and Regional Epilepsy Center, University of Washington, Seattle, WA, United Statesc-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family and are derived from three genes, Jnk1-3. These kinases are involved in cellular responses to homeostatic insults, such as inflammation and apoptosis. Furthermore, increased JNK expression and activation are associated with debilitating neurodegenerative diseases, including Alzheimer’s and Parkinson’s. We previously reported elevated levels of phosphorylated JNK (pJNK), indicative of JNK hyperactivation, in the CA1 hippocampus of chronically epileptic rats. We also showed that pharmacological inhibition of JNK activity reduced seizure frequency in a dose-dependent fashion (Tai TY et al., Neuroscience, 2017). Building on these observations, the objectives of this current study were to investigate the timeline of JNK activation during epileptogenesis, and to identify the JNK isoform(s) that undergo hyperactivation in the chronic epilepsy stage. Western blotting analysis of CA1 hippocampal homogenates showed JNK hyperactivation only during the chronic phase of epilepsy (6–9 weeks post-status epilepticus), and not in earlier stages of epileptogenesis (1 h, 1 day, and 1 week post-status epilepticus). After enrichment for pJNK by immunoprecipitation, we identified JNK2 as the only significantly hyperactivated JNK isoform, with expression of the 54 kDa pJNK2 variant elevated to a greater extent than the 46 kDa pJNK2 variant. Expression of the total amounts of both JNK2 variants (phosphorylated plus non-phosphorylated) was reduced in epilepsy, however, suggesting that activation of upstream phosphorylation pathways was responsible for JNK2 hyperactivation. Since our prior work demonstrated that pharmacological inhibition of JNK activation had an antiepileptic effect, JNK2 hyperactivation is therefore likely a pathological event that promotes seizure occurrences. This investigation provides evidence that JNK2 is selectively hyperactivated in epilepsy and thus may be a novel and selective antiepileptic target.http://www.sciencedirect.com/science/article/pii/S2451830120300029EpilepsyEpileptogenesisJNKPhosphorylationStatus epilepticusPilocarpine |
| spellingShingle | A.N. Parikh F.A. Concepcion M.N. Khan R.D. Boehm O.C. Poolos A. Dhami N.P. Poolos Selective hyperactivation of JNK2 in an animal model of temporal lobe epilepsy IBRO Reports Epilepsy Epileptogenesis JNK Phosphorylation Status epilepticus Pilocarpine |
| title | Selective hyperactivation of JNK2 in an animal model of temporal lobe epilepsy |
| title_full | Selective hyperactivation of JNK2 in an animal model of temporal lobe epilepsy |
| title_fullStr | Selective hyperactivation of JNK2 in an animal model of temporal lobe epilepsy |
| title_full_unstemmed | Selective hyperactivation of JNK2 in an animal model of temporal lobe epilepsy |
| title_short | Selective hyperactivation of JNK2 in an animal model of temporal lobe epilepsy |
| title_sort | selective hyperactivation of jnk2 in an animal model of temporal lobe epilepsy |
| topic | Epilepsy Epileptogenesis JNK Phosphorylation Status epilepticus Pilocarpine |
| url | http://www.sciencedirect.com/science/article/pii/S2451830120300029 |
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