Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice

The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains NMDA receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promote c-Abl phosphorylation and disrupting c-Abl activity leads to fewer seizures, increase latency towards SE, and improve animal survival.Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improve central nervous system permeability. Neurotinib-administered mice have fewer seizures and improve survival following SE induction with pilocarpine. Our findings reveal c-Abl kinase activation as key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures to investigate in rodents and humans.