| Autor: |
América Chandía-Cristi, Daniela A. Gutiérrez, Andrés E. Dulcey, Marcelo Lara, Lina Vargas, Yi-Han Lin, Pablo Jimenez-Muñoz, Gabriela Larenas, Xin Xu, Amy Wang, Ashley Owens, Christopher Dextras, YuChi Chen, Claudio Pinto, Tamara Marín, Hugo Almarza-Salazar, Keryma Acevedo, Gonzalo I. Cancino, Xin Hu, Patricio Rojas, Marc Ferrer, Noel Southall, Mark J. Henderson, Silvana Zanlungo, Juan J. Marugan, Alejandra Álvarez R |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 43, Iss 5, Pp 114144- (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2024.114144 |
| Popis: |
Summary: 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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