Ruxolitinib-dependent reduction of seizure load and duration is accompanied by spatial memory improvement in the rat pilocarpine model of temporal lobe epilepsy
Molecules with optimized pharmacokinetic properties selectively aimed at the inhibition of STAT3 phosphorylation in brain have recently emerged as potential disease modifying therapies for epilepsy. In the current study, pharmacological inhibition of JAK1/2 with the orally available, FDA-approved dr...
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Elsevier
2025-03-01
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| Series: | Neurotherapeutics |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878747924001934 |
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| author | Andrew Carrel Eleonora Napoli Kathryn Hixson Jessica Carlsen Yasmin Cruz Del Angel Dana Strode Nicolas Busquet Vijay Kumar Michael F. Wempe Shelley J. Russek Amy R. Brooks-Kayal |
| author_facet | Andrew Carrel Eleonora Napoli Kathryn Hixson Jessica Carlsen Yasmin Cruz Del Angel Dana Strode Nicolas Busquet Vijay Kumar Michael F. Wempe Shelley J. Russek Amy R. Brooks-Kayal |
| author_sort | Andrew Carrel |
| collection | DOAJ |
| description | Molecules with optimized pharmacokinetic properties selectively aimed at the inhibition of STAT3 phosphorylation in brain have recently emerged as potential disease modifying therapies for epilepsy. In the current study, pharmacological inhibition of JAK1/2 with the orally available, FDA-approved drug ruxolitinib, produced nearly complete inhibition of hippocampal STAT3 phosphorylation, and reduced the expression of its downstream target Cyclin D1, when administered to rats 30 min and 3 h after onset of pilocarpine-induced status epilepticus (SE). This effect was accompanied by significantly shorter seizure duration and lower overall seizure frequency throughout the 4 weeks of EEG recording, but did not completely prevent the development of epilepsy in ruxolitinib-treated male rats. Compared to DMSO-treated animals, administration of ruxolitinib also improved memory (Y maze) but did not impact motor function (open field) following SE. Taken together with our previous findings, the results of this study provide further evidence that inhibition of the JAK/STAT pathway may be a promising disease modifying strategy to reduce severity of acquired epilepsy after brain injury, but also point to the need to better understand and optimize inhibitors of this pathway. |
| format | Article |
| id | doaj-art-39cba2e39dad4f88ac8efbfde0c6eea4 |
| institution | DOAJ |
| issn | 1878-7479 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurotherapeutics |
| spelling | doaj-art-39cba2e39dad4f88ac8efbfde0c6eea42025-08-20T02:55:25ZengElsevierNeurotherapeutics1878-74792025-03-01222e0050610.1016/j.neurot.2024.e00506Ruxolitinib-dependent reduction of seizure load and duration is accompanied by spatial memory improvement in the rat pilocarpine model of temporal lobe epilepsyAndrew Carrel0Eleonora Napoli1Kathryn Hixson2Jessica Carlsen3Yasmin Cruz Del Angel4Dana Strode5Nicolas Busquet6Vijay Kumar7Michael F. Wempe8Shelley J. Russek9Amy R. Brooks-Kayal10Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USADepartment of Neurology, University of California Davis School of Medicine, Sacramento, CA, USAGraduate Program for Neuroscience, Center for Systems Neuroscience, Boston University, Boston, MA, USADepartment of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USADepartment of Neurology, University of California Davis School of Medicine, Sacramento, CA, USADepartment of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USADepartment of Neurology, University of Colorado School of Medicine, Aurora, CO, USADepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz, Aurora, CO, USADepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz, Aurora, CO, USA; Department of Chemistry, Kentucky State University, Frankfort, KY, USAGraduate Program for Neuroscience, Center for Systems Neuroscience, Boston University, Boston, MA, USA; Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USADepartment of Neurology, University of California Davis School of Medicine, Sacramento, CA, USA; Corresponding author.Molecules with optimized pharmacokinetic properties selectively aimed at the inhibition of STAT3 phosphorylation in brain have recently emerged as potential disease modifying therapies for epilepsy. In the current study, pharmacological inhibition of JAK1/2 with the orally available, FDA-approved drug ruxolitinib, produced nearly complete inhibition of hippocampal STAT3 phosphorylation, and reduced the expression of its downstream target Cyclin D1, when administered to rats 30 min and 3 h after onset of pilocarpine-induced status epilepticus (SE). This effect was accompanied by significantly shorter seizure duration and lower overall seizure frequency throughout the 4 weeks of EEG recording, but did not completely prevent the development of epilepsy in ruxolitinib-treated male rats. Compared to DMSO-treated animals, administration of ruxolitinib also improved memory (Y maze) but did not impact motor function (open field) following SE. Taken together with our previous findings, the results of this study provide further evidence that inhibition of the JAK/STAT pathway may be a promising disease modifying strategy to reduce severity of acquired epilepsy after brain injury, but also point to the need to better understand and optimize inhibitors of this pathway.http://www.sciencedirect.com/science/article/pii/S1878747924001934EpilepsyHippocampusMemoryPilocarpine rat modelRuxolitinibSeizure |
| spellingShingle | Andrew Carrel Eleonora Napoli Kathryn Hixson Jessica Carlsen Yasmin Cruz Del Angel Dana Strode Nicolas Busquet Vijay Kumar Michael F. Wempe Shelley J. Russek Amy R. Brooks-Kayal Ruxolitinib-dependent reduction of seizure load and duration is accompanied by spatial memory improvement in the rat pilocarpine model of temporal lobe epilepsy Neurotherapeutics Epilepsy Hippocampus Memory Pilocarpine rat model Ruxolitinib Seizure |
| title | Ruxolitinib-dependent reduction of seizure load and duration is accompanied by spatial memory improvement in the rat pilocarpine model of temporal lobe epilepsy |
| title_full | Ruxolitinib-dependent reduction of seizure load and duration is accompanied by spatial memory improvement in the rat pilocarpine model of temporal lobe epilepsy |
| title_fullStr | Ruxolitinib-dependent reduction of seizure load and duration is accompanied by spatial memory improvement in the rat pilocarpine model of temporal lobe epilepsy |
| title_full_unstemmed | Ruxolitinib-dependent reduction of seizure load and duration is accompanied by spatial memory improvement in the rat pilocarpine model of temporal lobe epilepsy |
| title_short | Ruxolitinib-dependent reduction of seizure load and duration is accompanied by spatial memory improvement in the rat pilocarpine model of temporal lobe epilepsy |
| title_sort | ruxolitinib dependent reduction of seizure load and duration is accompanied by spatial memory improvement in the rat pilocarpine model of temporal lobe epilepsy |
| topic | Epilepsy Hippocampus Memory Pilocarpine rat model Ruxolitinib Seizure |
| url | http://www.sciencedirect.com/science/article/pii/S1878747924001934 |
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