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

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 <i>in vitro</i> 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.癫痫发作的潜在分子机制至今仍未完全阐明，但其对于开发癫痫的有效治疗手段至关重要。本研究表明，在兴奋性毒性的体外（in vitro）模型中，抑制c-Abl酪氨酸激酶（c-Abl tyrosine kinase）可阻断细胞凋亡、减少树突棘丢失，并维持NMDA受体2B亚基（NR2B）的磷酸化水平。在小鼠体内，毛果芸香碱诱导的癫痫持续状态（SE）可促进c-Abl的磷酸化；而阻断c-Abl的活性，则可减少癫痫发作次数、延长癫痫持续状态的发作潜伏期，并提升小鼠存活率。目前临床使用的c-Abl抑制剂存在选择性不足、血脑屏障穿透性较差的问题。本研究采用的变构c-Abl抑制剂neurotinib（神经替尼）具备优异的药效活性、选择性与药代动力学特性，且中枢神经系统穿透性大幅提升。给予neurotinib的小鼠在经毛果芸香碱诱导癫痫持续状态后，癫痫发作次数更少且存活率更高。本研究结果证实，c-Abl激酶的激活是癫痫发作的关键驱动因素，并凸显了抑制c-Abl活性在预防类癫痫发作中的作用，可为啮齿类动物及人类的相关研究提供参考。