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

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dc.article.number114144
dc.catalogadoraba
dc.contributor.authorChandía Cristi, América Valeska
dc.contributor.authorGutiérrez García, Daniela A.
dc.contributor.authorDulcey, Andrés E.
dc.contributor.authorLara, Marcelo
dc.contributor.authorVargas Rojas, Lina Marcela
dc.contributor.authorLin, Yi-Han
dc.contributor.authorJiménez Muñoz, Pablo Salvador
dc.contributor.authorLarenas Barrera, Gabriela Paz
dc.contributor.authorXu, Xin
dc.contributor.authorWang, Amy
dc.contributor.authorOwens, Ashley
dc.contributor.authorDextras, Christopher
dc.contributor.authorChen, YuChi
dc.contributor.authorPinto, Claudio
dc.contributor.authorMarín Marín, Tamara Alejandra
dc.contributor.authorAlmarza Salazar, Hugo Alcester
dc.contributor.authorAcevedo, Keryma
dc.contributor.authorCancino Lobos, Gonzalo Ignacio
dc.contributor.authorHu, Xin
dc.contributor.authorRojas, Patricio
dc.contributor.authorFerrer, Marc
dc.contributor.authorSouthall, Noel
dc.contributor.authorHenderson, Mark J.
dc.contributor.authorZanlungo Matsuhiro, Silvana
dc.contributor.authorMarugan, Juan J.
dc.contributor.authorÁlvarez Rojas, Alejandra
dc.date.accessioned2024-05-10T19:32:12Z
dc.date.available2024-05-10T19:32:12Z
dc.date.issued2024
dc.description.abstractThe 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.
dc.description.funderCIBEM-UC
dc.description.funderANID
dc.description.funderYale School of Medicine
dc.description.funderNational Center for Advancing Translational Sciences
dc.description.funderFONDECYT
dc.description.funderFONDEF
dc.description.funderNIH
dc.fechaingreso.objetodigital2024-05-10
dc.fuente.origenSCOPUS
dc.identifier.doi10.1016/j.celrep.2024.114144
dc.identifier.issn2211-1247
dc.identifier.scopusidSCOPUS_ID:85191015227
dc.identifier.urihttps://doi.org/10.1016/j.celrep.2024.114144
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/85549
dc.information.autorucEscuela de Medicina; Zanlungo Matsuhiro, Silvana; 0000-0001-8383-9829; 72650
dc.information.autorucFacultad de Ciencias Biológicas; Álvarez Rojas, Alejandra; 0000-0002-8129-9280; 83681
dc.issue.numero5
dc.language.isoen
dc.nota.accesocontenido completo
dc.publisherElsevier B.V.
dc.revistaCell Reports
dc.rightsacceso restringido
dc.subjectc-Abl tyrosine kinase
dc.subjectSeizures
dc.subjectEpilepsy
dc.subjectAnti-convulsive drug
dc.subjectNMDA receptor
dc.subjectNeuronal death
dc.subject.ddc570
dc.subject.deweyBiologíaes_ES
dc.titleProphylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice
dc.typeartículo
dc.volumen43
sipa.codpersvinculados72650
sipa.codpersvinculados83681
sipa.trazabilidadSCOPUS;2024-05-05
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