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Lestaurtinib (CEP-701) attenuates "second hit" kainic acid-induced seizures following early life hypoxic seizures
Makram Obeid1, Evan C Rosenberg2, Peter M Klein2
1Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, USA; Harvard Medical School, USA.
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.
Insights
Hypoxic seizures increase brain TrkB signaling in developing rats. The drug lestaurtinib (CEP-701) reversed this signaling and reduced seizure susceptibility, offering a potential therapy for pediatric epilepsy.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Epilepsy Research
Background:
- Tropomyosin-related kinase receptor B (TrkB) signaling is implicated in epileptogenesis.
- Understanding TrkB's role in the immature brain is crucial for developing epilepsy therapies.
Purpose of the Study:
- To investigate hippocampal TrkB phosphorylation following hypoxic seizures (HS) in developing rats.
- To evaluate the antiepileptogenic potential of lestaurtinib (CEP-701) in this model.
Main Methods:
- Assessed hippocampal phosphorylated TrkB (p-TrkB) levels via immunoblotting post-HS.
- Administered CEP-701 or vehicle to rat pups after HS.
- Evaluated susceptibility to kainic acid (KA)-induced seizures at P14.
Main Results:
- HS induced a transient 1.5-fold increase in hippocampal p-TrkB levels 12 hours post-insult.
- CEP-701 treatment normalized p-TrkB levels.
- CEP-701 attenuated the enhanced susceptibility to KA-induced seizures observed after HS.
Conclusions:
- TrkB activation is transiently increased following HS in the immature brain.
- Lestaurtinib (CEP-701) effectively reduces TrkB phosphorylation and subsequent seizure susceptibility.
- CEP-701 represents a promising, clinically translatable therapeutic strategy for preventing epileptogenesis in the immature brain.
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