title: Lestaurtinib (CEP-701) attenuates "second hit" kainic acid-induced seizures following early life hypoxic seizures.
abstract: 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.
authors.affiliation: Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, USA; Harvard Medical School, USA.
authors.forename: Makram
authors.initials: M
authors.lastname: Obeid
authors.affiliation: Department of Neurology, Division of Neuroscience, Boston Children's Hospital, USA.
authors.forename: Evan C
authors.initials: EC
authors.lastname: Rosenberg
authors.affiliation: Department of Neurology, Division of Neuroscience, Boston Children's Hospital, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Klein
authors.affiliation: Harvard Medical School, USA; Department of Neurology, Division of Neuroscience, Boston Children's Hospital, USA; Department of Neurology, University of Pennsylavania, Philadelphia, PA. Electronic address: frances.jensen@uphs.upenn.edu.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Jensen
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use*; D005663:Furans; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism; D007608:Kainic Acid; D008297:Male; D010766:Phosphorylation; D051381:Rats; D020318:Rats, Long-Evans; D020813:Receptor, trkB / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D002227:Carbazoles; D005663:Furans; C119379:lestaurtinib; D020813:Receptor, trkB; D007608:Kainic Acid
keywords: Epileptogenesis; Hypoxic seizures; Memory; Neonates; Tropomyosin-related kinase receptor; Tyrosine kinase receptor