Animals; Brain Injuries/therapy; Cell Differentiation; Humans; Infant, Newborn; Neural Stem Cells/metabolism; Transfection; Brain Injuries; Neural Stem Cells; Immunology; Cellular and Molecular Neuroscience; Cell Biology; Cancer Research
Abstract :
[en] Neural stem cells are activated within neurogenic niches in response to brain injuries. This results in the production of neuroblasts, which unsuccessfully attempt to migrate toward the damaged tissue. Injuries constitute a gliogenic/non-neurogenic niche generated by the presence of anti-neurogenic signals, which impair neuronal differentiation and migration. Kinases of the protein kinase C (PKC) family mediate the release of growth factors that participate in different steps of the neurogenic process, particularly, novel PKC isozymes facilitate the release of the neurogenic growth factor neuregulin. We have demonstrated herein that a plant derived diterpene, (EOF2; CAS number 2230806-06-9), with the capacity to activate PKC facilitates the release of neuregulin 1, and promotes neuroblasts differentiation and survival in cultures of subventricular zone (SVZ) isolated cells in a novel PKC dependent manner. Local infusion of this compound in mechanical cortical injuries induces neuroblast enrichment within the perilesional area, and noninvasive intranasal administration of EOF2 promotes migration of neuroblasts from the SVZ towards the injury, allowing their survival and differentiation into mature neurons, being some of them cholinergic and GABAergic. Our results elucidate the mechanism of EOF2 promoting neurogenesis in injuries and highlight the role of novel PKC isozymes as targets in brain injury regeneration.
Domínguez-García, Samuel ✱; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain
Geribaldi-Doldán, Noelia ✱; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain ; Departamento de Anatomía y Embriología Humanas, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain
Gómez Oliva, Ricardo ; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Molecular Regulation of Neurogenesis ; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain
Ruiz, Felix A ; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain ; Área de Nutrición, Facultad de Medicina Universidad de Cádiz, Cádiz, Spain
Carrascal, Livia; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain ; Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain
Bolívar, Jorge; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain ; Área de Bioquímica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Spain
Verástegui, Cristina; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain ; Departamento de Anatomía y Embriología Humanas, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain
Garcia-Alloza, Monica; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain
Macías-Sánchez, Antonio J; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain ; Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Spain
Hernández-Galán, Rosario; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain ; Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real, Spain
Nunez-Abades, Pedro; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain. pnunez@us.es ; Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain. pnunez@us.es
Castro, Carmen ; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain. carmen.castro@uca.es ; Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain. carmen.castro@uca.es
✱ These authors have contributed equally to this work.
Language :
English
Title :
A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries.
We dedicate this paper to our late colleague and friend, Dr. Maribel Murillo-Carretero, whose dedication and critical advice was very valuable to this work. This work was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (Grant Numbers RTI2018–099908-B-C21, and RTI2018–099908-BC21 MICINN/FEDER granted to CC and RHG respectively and BFU2016–75038R granted to MGA) and Consejería de Economía, Conocimiento, Empresas y Universidades Junta de Andalucía (grant number FEDER-ANDALUCÍA sol-2018–00106647-tra). We thank Antonio Torres for his technical assistance. We thank the Servicio de experimentación y producción animal (SEPA) de la Universidad de Cádiz as well as the Servicios Centrales de apoyo a la investigación en Ciencias de la Salud (SCICS) and Servicios centrales de Ciencia y tecnología (SC-ICYT) de la Universidad de Cádiz. We appreciate the assistance provided by Juan Luis Ribas and Modesto Carballo of the Servicio de Microscopia y Biología, respectively, of the Centro de Investigación, Tecnología e Innovación de la Universidad de Sevilla (CITIUS).
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