Browsing by Author "Vargas Rojas, Lina Marcela"

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    c-Abl Modulates AICD Dependent Cellular Responses: Transcriptional Induction and Apoptosis
    (2009) Vazquez, M. C.; Vargas Rojas, Lina Marcela; Inestrosa Cantín, Nibaldo; Álvarez Rojas, Alejandra
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    Oxidative stress activates the c-Abl/p73 proapoptotic pathway in Niemann-Pick type C neurons
    (2010) Klein Posternack, Andrés David; Maldonado Vera, Carola Patricia; Vargas Rojas, Lina Marcela; González Bustos, Marcela Paz; Robledo Plaza, Fermín Alberto; Pérez de Arce Guzman, Karen Andrea; Muñoz, Francisco J.; Hetz, Claudio; Álvarez, Alejandra R.; Zanlungo Matsuhiro, Silvana
    Niemann-Pick type C (NPC) is a neurodegenerative disease characterized by the intralysosomal accumulation of cholesterol leading to neuronal apoptosis. We have previously reported the activation of the c-Abl/p73 proapoptotic pathway in the cerebellum of NPC mice; however, upstream signals underlying the engagement of this pathway remain unknown. Here, we investigate the possible role of oxidative stress in the activation of c-Abl/p73 using different in vitro and in vivo NPC models. Our results indicate a close temporal correlation between the appearance of nitrotyrosine (N-Tyr; a post-translational tyrosine modification caused by oxidative stress) and the activation of c-Abl/p73 in NPC models. To test the functional role of oxidative stress in NPC, we have treated NPC neurons with the antioxidant NAC and observed a dramatic decrease of c-Abl/p73 activation and a reduction in the levels of apoptosis in NPC models. In conclusion, our data suggest that oxidative stress is the main upstream stimulus activating the c-Abl/p73 pathway and neuronal apoptosis in NPC neurons.
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    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.