Lestaurtinib (CEP-701) attenuates 'second hit' kainic acid-induced seizures following early life hypoxic seizures
| Autor: | Evan C. Rosenberg, Makram Obeid, Frances E. Jensen, Peter M. Klein |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
Kainic acid medicine.medical_specialty medicine.drug_class Carbazoles Tropomyosin receptor kinase B Hippocampal formation Biology Hippocampus Epileptogenesis Tyrosine-kinase inhibitor chemistry.chemical_compound Epilepsy Seizures Internal medicine medicine Animals Receptor trkB Rats Long-Evans Phosphorylation Furans Hypoxia Kainic Acid Lestaurtinib Kinase musculoskeletal neural and ocular physiology medicine.disease Rats Endocrinology nervous system Neurology chemistry Anticonvulsants Neurology (clinical) medicine.drug |
| Zdroj: | Epilepsy Research. 108:806-810 |
| ISSN: | 0920-1211 |
| Popis: | Tropomyosin-related kinase receptor B (TrkB) activation has been implicated in epileptogenesis. We investigated hippocampal levels of phosphorylated TrkB (p-TrkB) and potential antiepileptogenic actions of the tyrosine kinase inhibitor, lestaurtinib (CEP-701) in postnatal day 10 (P10) rat pups following hypoxic seizures (HS). Hippocampal expression of p-TrkB over total TrkB protein levels were assessed by immunoblot at 6, 12, or 24 h post-HS, and revealed a statistically significant and transient 1.5-fold increase in hippocampal p-TrkB 12 h post-HS compared to littermate normoxic controls. To investigate the effects of CEP-701, pups were treated with 2 doses of CEP-701 intraperitoneally (i.p.), 3 mg/kg/dose, immediately after and 12 h post-HS. P-TrkB levels and susceptibility to kainic acid (KA)-induced seizures at P14 were compared between post-HS CEP-701-treated pups, post-HS vehicle-treated pups and normoxic littermates. Post-treatment with CEP-701 reversed the increased TrkB phosphorylation to baseline normoxic levels and attenuated the HS-related enhanced susceptibility to KA-induced seizures at P14. Given its known clinical safety profile, CEP-701 is a promising clinically translatable therapy to prevent epileptogenesis in the immature brain. |
| Databáze: | OpenAIRE |
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