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Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice.
Chandía-Cristi, América; Gutiérrez, Daniela A; Dulcey, Andrés E; Lara, Marcelo; Vargas, Lina; Lin, Yi-Han; Jimenez-Muñoz, Pablo; Larenas, Gabriela; Xu, Xin; Wang, Amy; Owens, Ashley; Dextras, Christopher; Chen, YuChi; Pinto, Claudio; Marín, Tamara; Almarza-Salazar, Hugo; Acevedo, Keryma; Cancino, Gonzalo I; Hu, Xin; Rojas, Patricio; Ferrer, Marc; Southall, Noel; Henderson, Mark J; Zanlungo, Silvana; Marugan, Juan J; Álvarez R, Alejandra.
Afiliação
  • Chandía-Cristi A; Department of Cellular and Molecular Biology, Pontificia Universidad Católica de Chile, Portugal 49, Santiago, Chile.
  • Gutiérrez DA; Department of Cellular and Molecular Biology, Pontificia Universidad Católica de Chile, Portugal 49, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Portugal 49, Santiago, Chile.
  • Dulcey AE; Early Translation Branch, National Center for Advancing Translational Sciences (NCATS), NIH, 9800 Medical Center Drive, Rockville, MD, USA.
  • Lara M; Neuroscience Laboratory, Biology and Chemistry Faculty, Universidad de Santiago de Chile, Avenue Libertador Bernardo O'Higgins, Santiago 3363, Chile.
  • Vargas L; Department of Cellular and Molecular Biology, Pontificia Universidad Católica de Chile, Portugal 49, Santiago, Chile.
  • Lin YH; Early Translation Branch, National Center for Advancing Translational Sciences (NCATS), NIH, 9800 Medical Center Drive, Rockville, MD, USA.
  • Jimenez-Muñoz P; Department of Cellular and Molecular Biology, Pontificia Universidad Católica de Chile, Portugal 49, Santiago, Chile.
  • Larenas G; Department of Cellular and Molecular Biology, Pontificia Universidad Católica de Chile, Portugal 49, Santiago, Chile.
  • Xu X; Early Translation Branch, National Center for Advancing Translational Sciences (NCATS), NIH, 9800 Medical Center Drive, Rockville, MD, USA.
  • Wang A; Early Translation Branch, National Center for Advancing Translational Sciences (NCATS), NIH, 9800 Medical Center Drive, Rockville, MD, USA.
  • Owens A; Early Translation Branch, National Center for Advancing Translational Sciences (NCATS), NIH, 9800 Medical Center Drive, Rockville, MD, USA.
  • Dextras C; Early Translation Branch, National Center for Advancing Translational Sciences (NCATS), NIH, 9800 Medical Center Drive, Rockville, MD, USA.
  • Chen Y; Early Translation Branch, National Center for Advancing Translational Sciences (NCATS), NIH, 9800 Medical Center Drive, Rockville, MD, USA.
  • Pinto C; Department of Cellular and Molecular Biology, Pontificia Universidad Católica de Chile, Portugal 49, Santiago, Chile.
  • Marín T; Department of Cellular and Molecular Biology, Pontificia Universidad Católica de Chile, Portugal 49, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Portugal 49, Santiago, Chile.
  • Almarza-Salazar H; Department of Cellular and Molecular Biology, Pontificia Universidad Católica de Chile, Portugal 49, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Portugal 49, Santiago, Chile.
  • Acevedo K; Neurology Unit of Pediatric Division, Pontificia Universidad Católica de Chile, Avenue Libertador Bernardo O'Higgins 340, Santiago, Chile.
  • Cancino GI; Department of Cellular and Molecular Biology, Pontificia Universidad Católica de Chile, Portugal 49, Santiago, Chile.
  • Hu X; Early Translation Branch, National Center for Advancing Translational Sciences (NCATS), NIH, 9800 Medical Center Drive, Rockville, MD, USA.
  • Rojas P; Neuroscience Laboratory, Biology and Chemistry Faculty, Universidad de Santiago de Chile, Avenue Libertador Bernardo O'Higgins, Santiago 3363, Chile.
  • Ferrer M; Early Translation Branch, National Center for Advancing Translational Sciences (NCATS), NIH, 9800 Medical Center Drive, Rockville, MD, USA.
  • Southall N; Early Translation Branch, National Center for Advancing Translational Sciences (NCATS), NIH, 9800 Medical Center Drive, Rockville, MD, USA.
  • Henderson MJ; Early Translation Branch, National Center for Advancing Translational Sciences (NCATS), NIH, 9800 Medical Center Drive, Rockville, MD, USA.
  • Zanlungo S; Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Avenue Libertador Bernardo O'Higgins 340, Santiago, Chile. Electronic address: szanlungo@uc.cl.
  • Marugan JJ; Early Translation Branch, National Center for Advancing Translational Sciences (NCATS), NIH, 9800 Medical Center Drive, Rockville, MD, USA. Electronic address: maruganj@mail.nih.gov.
  • Álvarez R A; Department of Cellular and Molecular Biology, Pontificia Universidad Católica de Chile, Portugal 49, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Portugal 49, Santiago, Chile. Electronic address: aalvare
Cell Rep ; 43(5): 114144, 2024 May 28.
Article em En | MEDLINE | ID: mdl-38656874
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pilocarpina / Convulsões / Proteínas Proto-Oncogênicas c-abl Limite: Animals Idioma: En Revista: Cell Rep Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Chile País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pilocarpina / Convulsões / Proteínas Proto-Oncogênicas c-abl Limite: Animals Idioma: En Revista: Cell Rep Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Chile País de publicação: Estados Unidos