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Protein Kinase C Inhibition Mediates Neuroblast Enrichment in Mechanical Brain Injuries

Brain injuries of different etiologies lead to irreversible neuronal loss and persisting neuronal deficits. New therapeutic strategies are emerging to compensate neuronal damage upon brain injury. Some of these strategies focus on enhancing endogenous generation of neurons from neural stem cells (NS...

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Autores principales: García-Bernal, Francisco, Geribaldi-Doldán, Noelia, Domínguez-García, Samuel, Carrasco, Manuel, Murillo-Carretero, Maribel, Delgado-Ariza, Antonio, Díez-Salguero, Mónica, Verástegui, Cristina, Castro, Carmen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277931/
https://www.ncbi.nlm.nih.gov/pubmed/30542270
http://dx.doi.org/10.3389/fncel.2018.00462
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author García-Bernal, Francisco
Geribaldi-Doldán, Noelia
Domínguez-García, Samuel
Carrasco, Manuel
Murillo-Carretero, Maribel
Delgado-Ariza, Antonio
Díez-Salguero, Mónica
Verástegui, Cristina
Castro, Carmen
author_facet García-Bernal, Francisco
Geribaldi-Doldán, Noelia
Domínguez-García, Samuel
Carrasco, Manuel
Murillo-Carretero, Maribel
Delgado-Ariza, Antonio
Díez-Salguero, Mónica
Verástegui, Cristina
Castro, Carmen
author_sort García-Bernal, Francisco
collection PubMed
description Brain injuries of different etiologies lead to irreversible neuronal loss and persisting neuronal deficits. New therapeutic strategies are emerging to compensate neuronal damage upon brain injury. Some of these strategies focus on enhancing endogenous generation of neurons from neural stem cells (NSCs) to substitute the dying neurons. However, the capacity of the injured brain to produce new neurons is limited, especially in cases of extensive injury. This reduced neurogenesis is a consequence of the effect of signaling molecules released in response to inflammation, which act on intracellular pathways, favoring gliogenesis and preventing recruitment of neuroblasts from neurogenic regions. Protein kinase C (PKC) is a family of intracellular kinases involved in several of these gliogenic signaling pathways. The aim of this study was to analyze the role of PKC isozymes in the generation of neurons from neural progenitor cells (NPCs) in vitro and in vivo in brain injuries. PKC inhibition in vitro, in cultures of NPC isolated from the subventricular zone (SVZ) of postnatal mice, leads differentiation towards a neuronal fate. This effect is not mediated by classical or atypical PKC. On the contrary, this effect is mediated by novel PKCε, which is abundantly expressed in NPC cultures under differentiation conditions. PKCε inhibition by siRNA promotes neuronal differentiation and reduces glial cell differentiation. On the contrary, inhibition of PKCθ exerts a small anti-gliogenic effect and reverts the effect of PKCε inhibition on neuronal differentiation when both siRNAs are used in combination. Interestingly, in cortical brain injuries we have found expression of almost all PKC isozymes found in vitro. Inhibition of PKC activity in this type of injuries leads to neuronal production. In conclusion, these findings show an effect of PKCε in the generation of neurons from NPC in vitro, and they highlight the role of PKC isozymes as targets to produce neurons in brain lesions.
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spelling pubmed-62779312018-12-12 Protein Kinase C Inhibition Mediates Neuroblast Enrichment in Mechanical Brain Injuries García-Bernal, Francisco Geribaldi-Doldán, Noelia Domínguez-García, Samuel Carrasco, Manuel Murillo-Carretero, Maribel Delgado-Ariza, Antonio Díez-Salguero, Mónica Verástegui, Cristina Castro, Carmen Front Cell Neurosci Neuroscience Brain injuries of different etiologies lead to irreversible neuronal loss and persisting neuronal deficits. New therapeutic strategies are emerging to compensate neuronal damage upon brain injury. Some of these strategies focus on enhancing endogenous generation of neurons from neural stem cells (NSCs) to substitute the dying neurons. However, the capacity of the injured brain to produce new neurons is limited, especially in cases of extensive injury. This reduced neurogenesis is a consequence of the effect of signaling molecules released in response to inflammation, which act on intracellular pathways, favoring gliogenesis and preventing recruitment of neuroblasts from neurogenic regions. Protein kinase C (PKC) is a family of intracellular kinases involved in several of these gliogenic signaling pathways. The aim of this study was to analyze the role of PKC isozymes in the generation of neurons from neural progenitor cells (NPCs) in vitro and in vivo in brain injuries. PKC inhibition in vitro, in cultures of NPC isolated from the subventricular zone (SVZ) of postnatal mice, leads differentiation towards a neuronal fate. This effect is not mediated by classical or atypical PKC. On the contrary, this effect is mediated by novel PKCε, which is abundantly expressed in NPC cultures under differentiation conditions. PKCε inhibition by siRNA promotes neuronal differentiation and reduces glial cell differentiation. On the contrary, inhibition of PKCθ exerts a small anti-gliogenic effect and reverts the effect of PKCε inhibition on neuronal differentiation when both siRNAs are used in combination. Interestingly, in cortical brain injuries we have found expression of almost all PKC isozymes found in vitro. Inhibition of PKC activity in this type of injuries leads to neuronal production. In conclusion, these findings show an effect of PKCε in the generation of neurons from NPC in vitro, and they highlight the role of PKC isozymes as targets to produce neurons in brain lesions. Frontiers Media S.A. 2018-11-27 /pmc/articles/PMC6277931/ /pubmed/30542270 http://dx.doi.org/10.3389/fncel.2018.00462 Text en Copyright © 2018 García-Bernal, Geribaldi-Doldán, Domínguez-García, Carrasco, Murillo-Carretero, Delgado-Ariza, Díez-Salguero, Verástegui and Castro. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
García-Bernal, Francisco
Geribaldi-Doldán, Noelia
Domínguez-García, Samuel
Carrasco, Manuel
Murillo-Carretero, Maribel
Delgado-Ariza, Antonio
Díez-Salguero, Mónica
Verástegui, Cristina
Castro, Carmen
Protein Kinase C Inhibition Mediates Neuroblast Enrichment in Mechanical Brain Injuries
title Protein Kinase C Inhibition Mediates Neuroblast Enrichment in Mechanical Brain Injuries
title_full Protein Kinase C Inhibition Mediates Neuroblast Enrichment in Mechanical Brain Injuries
title_fullStr Protein Kinase C Inhibition Mediates Neuroblast Enrichment in Mechanical Brain Injuries
title_full_unstemmed Protein Kinase C Inhibition Mediates Neuroblast Enrichment in Mechanical Brain Injuries
title_short Protein Kinase C Inhibition Mediates Neuroblast Enrichment in Mechanical Brain Injuries
title_sort protein kinase c inhibition mediates neuroblast enrichment in mechanical brain injuries
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277931/
https://www.ncbi.nlm.nih.gov/pubmed/30542270
http://dx.doi.org/10.3389/fncel.2018.00462
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