RESUMEN
Recent findings suggest a significant role of the brain-derived neurotrophic factor (BDNF) as a mediator of brain regeneration following a stab injury in zebrafish. Since BDNF has been implicated in many physiological processes, we hypothesized that these processes are affected by brain injury in zebrafish. Hence, we examined the impact of stab injury on oxidative stress and apoptosis in the adult zebrafish brain. Stab wound injury (SWI) was induced in the right telencephalic hemisphere of the adult zebrafish brain and examined at different time points. The biochemical variables of oxidative stress insult and transcript levels of antioxidant genes were assessed to reflect upon the oxidative stress levels in the brain. Immunohistochemistry was performed to detect the levels of early apoptotic marker protein cleaved caspase-3, and the transcript levels of pro-apoptotic and anti-apoptotic genes were examined to determine the effect of SWI on apoptosis. The activity of antioxidant enzymes, the level of lipid peroxidation (LPO) and reduced glutathione (GSH) were significantly increased in the injured fish brain. SWI also enhanced the expression of cleaved caspase-3 protein and apoptosis-related gene transcripts. Our results indicate induction of oxidative stress and apoptosis in the telencephalon of adult zebrafish brain by SWI. These findings contribute to the overall understanding of the pathophysiology of traumatic brain injury and adult neurogenesis in the zebrafish model and raise new questions about the compensatory physiological mechanisms in response to traumatic brain injury in the adult zebrafish brain.
Asunto(s)
Lesiones Encefálicas/fisiopatología , Regeneración Cerebral/fisiología , Estrés Oxidativo/fisiología , Animales , Apoptosis/genética , Encéfalo/metabolismo , Lesiones Encefálicas/genética , Lesiones Encefálicas/metabolismo , Lesiones Traumáticas del Encéfalo , Regeneración Cerebral/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Regeneración Nerviosa/fisiología , Neurogénesis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Telencéfalo/lesiones , Telencéfalo/metabolismo , Telencéfalo/fisiopatología , Heridas Punzantes/metabolismo , Heridas Punzantes/fisiopatología , Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
The considerable post-traumatic brain recovery in fishes makes them a useful model for studying the mechanisms that provide reparative neurogenesis, which is poorly represented in mammals. After a mechanical injury to the telencephalon in adult fish, lost neurons are actively replaced due to the proliferative activity of neuroepithelial cells and radial glia in the neurogenic periventricular zone. However, it is not enough clear which signaling mechanisms are involved in the activation of adult neural stem cells (aNSC) after the injury (reactive proliferation) and in the production of new neurons (regenerative neurogenesis) from progenitor cells (NPC). In juvenile Pacific salmon, the predominant type of NSCs in the telencephalon are neuroepithelial cells corresponding to embryonic NSCs. Expression of glutamine synthetase (GS), a NSC molecular marker, was detected in the neuroepithelial cells of the pallium and subpallium of juvenile chum salmon, Oncorhynchus keta. At 3 days after a traumatic brain injury (TBI) in juvenile chum salmon, the GS expression was detected in the radial glia corresponding to aNSC in the pallium and subpallium. The maximum density of distribution of GS+ radial glia was found in the dorsal pallial region. Hydrogen sulfide (H2S) is a proneurogenic factor that reduces oxidative stress and excitotoxicity effects, along with the increased GS production in the brain cells of juvenile chum salmon. In the fish brain, H2S producing by cystathionine ß-synthase in neurogenic zones may be involved in maintaining the microenvironment that provides optimal conditions for the functioning of neurogenic niches during constitutive neurogenesis. After injury, H2S can determine cell survivability, providing a neuroprotective effect in the area of injury and reducing the process of glutamate excitotoxicity, acting as a signaling molecule involved in changing the neurogenic environment, which leads to the reactivation of neurogenic niches and cell regeneration programs. The results of studies on the control of the expression of regulatory Sonic Hedgehog genes (Shh) and the transcription factors Paired Box2 (Pax2) regulated by them are still insufficient. A comparative analysis of Pax2 expression in the telencephalon of intact chum salmon showed the presence of constitutive patterns of Pax2 expression in neurogenic areas and non-neurogenic parenchymal zones of the pallium and subpallium. After mechanical injury, the patterns of Pax2 expression changed, and the amount of Pax2+ decreased (p < 0.05) in lateral (Dl), medial (Dm) zones of the pallium, and the lateral zone (Vl) of the subpallium compared to the control. We believe that the decrease in the expression of Pax2 may be caused by the inhibitory effect of the Pax6 transcription factor, whose expression in the juvenile salmon brain increases upon injury.
Asunto(s)
Lesiones Encefálicas/genética , Regeneración Cerebral/genética , Cistationina betasintasa/genética , Proteínas de Peces/genética , Glutamato-Amoníaco Ligasa/genética , Factor de Transcripción PAX2/genética , Telencéfalo/metabolismo , Células Madre Adultas/citología , Células Madre Adultas/metabolismo , Animales , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Diferenciación Celular , Proliferación Celular , Cistationina betasintasa/metabolismo , Proteínas de Peces/metabolismo , Regulación de la Expresión Génica , Glutamato-Amoníaco Ligasa/metabolismo , Ácido Glutámico/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Sulfuro de Hidrógeno/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Células Neuroepiteliales/citología , Células Neuroepiteliales/metabolismo , Neurogénesis/genética , Neuroglía/citología , Neuroglía/metabolismo , Neuronas/citología , Neuronas/metabolismo , Oncorhynchus keta , Factor de Transcripción PAX2/metabolismo , Factor de Transcripción PAX6/genética , Factor de Transcripción PAX6/metabolismo , Telencéfalo/lesiones , Telencéfalo/patologíaRESUMEN
Acute ischemia-reperfusion (IR)-induced brain injury is further exacerbated by a series of slower secondary pathogenic events, including delayed apoptosis due to neurotrophic factor deficiency. Neuritin, a neurotrophic factor regulating nervous system development and plasticity, is a potential therapeutic target for treatment of IR injury. In this study, Neuritin-overexpressing transgenic (Tg) mice were produced by pronuclear injection and offspring with high overexpression used to generate a line with stable inheritance for testing the neuroprotective capacity of Neuritin against transient global ischemia (TGI). Compared to wild-type mice, transgenic mice demonstrated reduced degradation of the DNA repair factor poly [ADP-ribose] polymerase 1 (PARP 1) in the hippocampus, indicating decreased hippocampal apoptosis rate, and a greater number of surviving hippocampal neurons during the first week post-TGI. In addition, Tg mice showed increased expression of the regeneration markers NF-200, synaptophysin, and GAP-43, and improved recovery of spatial learning and memory. Our findings exhibited that the window of opportunity of neural recovery in Neuritin transgenic mice group had a tendency to move ahead after TGI, which indicated that Neuritin can be used as a potential new therapeutic strategy for improving the outcome of cerebral ischemia injury.
Asunto(s)
Regeneración Cerebral/genética , Encéfalo/fisiopatología , Memoria , Neuronas/metabolismo , Neuropéptidos/genética , Daño por Reperfusión/fisiopatología , Aprendizaje Espacial , Animales , Apoptosis , Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Arteria Carótida Común , Supervivencia Celular , Femenino , Proteína GAP-43/metabolismo , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Hipocampo/citología , Hipocampo/metabolismo , Masculino , Ratones , Ratones Transgénicos , Prueba del Laberinto Acuático de Morris , Proteínas de Neurofilamentos/metabolismo , Neuropéptidos/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , ARN Mensajero/metabolismo , Ratas , Recuperación de la Función , Daño por Reperfusión/metabolismo , Sinaptofisina/metabolismoRESUMEN
Brain regeneration and tumorigenesis are complex processes involving in changes in chromatin structure to regulate cellular states at the molecular and genomic level. The modulation of chromatin structure dynamics is critical for maintaining progenitor cell plasticity, growth and differentiation. Oligodendrocyte precursor cells (OPC) can be differentiated into mature oligodendrocytes, which produce myelin sheathes to permit saltatory nerve conduction. OPCs and their primitive progenitors such as pri-OPC or pre-OPC are highly adaptive and plastic during injury repair or brain tumor formation. Recent studies indicate that chromatin modifications and epigenetic homeostasis through histone modifying enzymes shape genomic regulatory landscape conducive to OPC fate specification, lineage differentiation, maintenance of myelin sheaths, as well as brain tumorigenesis. Thus, histone modifications can be convergent mechanisms in regulating OPC plasticity and malignant transformation. In this review, we will focus on the impact of histone modifying enzymes in modulating OPC plasticity during normal development, myelin regeneration and tumorigenesis.