Browsing by Author "Jiménez Muñoz, Pablo Salvador"

Now showing 1 - 1 of 1
  • No Thumbnail Available
    Item
    Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice
    (Elsevier B.V., 2024) Chandía Cristi, América Valeska; Gutiérrez García, Daniela A.; Dulcey, Andrés E.; Lara, Marcelo; Vargas Rojas, Lina Marcela; Lin, Yi-Han; Jiménez Muñoz, Pablo Salvador; Larenas Barrera, Gabriela Paz; Xu, Xin; Wang, Amy; Owens, Ashley; Dextras, Christopher; Chen, YuChi; Pinto, Claudio; Marín Marín, Tamara Alejandra; Almarza Salazar, Hugo Alcester; Acevedo, Keryma; Cancino Lobos, Gonzalo Ignacio; Hu, Xin; Rojas, Patricio; Ferrer, Marc; Southall, Noel; Henderson, Mark J.; Zanlungo Matsuhiro, Silvana; Marugan, Juan J.; Álvarez Rojas, Alejandra
    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 N-methyl-D-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved 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 improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.