Injury and Repair in the Immature Brain

Blomgren, Klas; Hagberg, Henrik

doi:10.1007/s12975-013-0256-3

Cited by 4 publications

(5 citation statements)

References 15 publications

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“…Additionally, a significant number of pathophysiological differences exist between adults and newborns, including differences in their responses to hypoxic ischemic injury and its treatments (Blomgren and Hagberg, 2013; Vexler et al, 2006a; Vexler et al, 2006b). Finally, G-CSF provides increased neuroprotection from ischemic brain injury in neonates (Charles et al, 2012) compared to adults (Solaroglu et al, 2009); G-CSF treatment (50µg/kg) caused a 50% reduction in infarction volume following neonatal HI (Charles et al, 2012) compared to a 22% reduction following adult cerebral ischemia (Solaroglu et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

G-CSF attenuates neuroinflammation and stabilizes the blood–brain barrier via the PI3K/Akt/GSK-3β signaling pathway following neonatal hypoxia-ischemia in rats

McBride

Doycheva

et al. 2015

Experimental Neurology

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Objective Neonatal hypoxia occurs in approximately 60% of premature births and is associated with a multitude of neurological disorders. While various treatments have been developed, translating them from bench to bedside has been limited. We previously showed G-CSF administration was neuroprotective in a neonatal hypoxia-ischemia rat pup model, leading us to hypothesize that G-CSF inactivation of GSK-3β via the PI3K/Akt pathway may attenuate neuroinflammation and stabilize the Blood-Brain Barrier (BBB). Methods P10 Sprague-Dawley rat pups were subjected to unilateral carotid artery ligation followed by hypoxia for 2.5 hours. We assessed inflammation by measuring expression levels of IKKβ, NF-κB, TNF-α, IL-1β, IL-10, and IL-12, as well as neutrophil infiltration. BBB stabilization was evaluated by measuring Evans blue extravasation, and Western blot analysis of Claudin-3, Claudin-5, ICAM-1 and VCAM-1. Measurements and Main Results First, the time course study showed that p-β-Catenin/β-Catenin, IKKβ, and NF-κB expression levels peaked at 48 hours post-HI. Knockdown of GSK-3β with siRNA prevented the HI-induced increase of p-β-Catenin/β-Catenin, IKKβ, and NF-κB expression levels 48 hours after HI. G-CSF treatment reduced brain water content and neuroinflammation by downregulating IKKβ, NF-κB, TNF-α, IL-1β, and IL-12 and upregulating IL-10, thereby reducing neutrophil infiltration. Additionally, G-CSF stabilizes the BBB by downregulating VCAM-1 and ICAM-1, as well as upregulating Claudins 3 and 5 in endothelial cells. G-CSFR knockdown by siRNA and Akt inhibition by Wortmannin reversed G-CSF’s neuroprotective effects. Conclusions We demonstrate G-CSF plays a pivotal role in attenuating neuroinflammation and BBB disruption following HI by inactivating GSK-3β through the PI3K/Akt pathway.

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Section: Discussionmentioning

confidence: 99%

G-CSF attenuates neuroinflammation and stabilizes the blood–brain barrier via the PI3K/Akt/GSK-3β signaling pathway following neonatal hypoxia-ischemia in rats

McBride

Doycheva

et al. 2015

Experimental Neurology

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“…As a family of signaling proteins, TFG-β proteins are involved in regulating a variety of molecular pathways, including cell proliferation and differentiation, immunity, inflammation cascades, and tissue repair [139-153]. They appear in both animals and humans, and both systemically and in the central nervous system (CNS) [139-152].…”

Section: Neurovascular Unitmentioning

confidence: 99%

Neonatal Brain Hemorrhage (NBH) of Prematurity: Translational Mechanisms of the Vascular-Neural Network

Lekic¹,

Klebe²,

Poblete³

et al. 2015

CMC

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Neonatal brain hemorrhage (NBH) of prematurity is an unfortunate consequence of preterm birth. Complications result in shunt dependence and long-term structural changes such as post-hemorrhagic hydrocephalus, periventricular leukomalacia, gliosis, and neurological dysfunction. Several animal models are available to study this condition, and many basic mechanisms, etiological factors, and outcome consequences, are becoming understood. NBH is an important clinical condition, of which treatment may potentially circumvent shunt complication, and improve functional recovery (cerebral palsy, and cognitive impairments). This review highlights key pathophysiological findings of the neonatal vascular-neural network in the context of molecular mechanisms targeting the post-hemorrhagic hydrocephalus affecting this vulnerable infant population.

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“…Studies have shown that mitochondrial outer membrane permeabilization is the predominant form of apoptosis in the immature brain in comparison to the adult 40 , 41 . Mitochondria are implicated in numerous processes of the developing newborn brain (cellular powerhouse, programmed cell death, inflammation, formation of reactive oxygen species etc) 22 , 23 , 42 , 43 . Understanding of the mitochondria-mediated cell death pathways and their regulation is crucial in order to identify targets and therapies to alleviate injury of the developing brain.…”

Section: Discussionmentioning

confidence: 99%

“…In the term neonate affected by HI encephalopathy, the main areas of the brain affected are the hippocampus, sensory and motor cortex, basal ganglia, thalamus, and brain stem 22 . The HI insult may disrupt the formation of central motor pathways and alter the developmental plasticity of the newborn brain resulting in significant long term disabilities 23 .…”

Section: Introductionmentioning

confidence: 99%

Effect of Src Kinase inhibition on Cytochrome c, Smac/DIABLO and Apoptosis Inducing Factor (AIF) Following Cerebral Hypoxia-Ischemia in Newborn Piglets

Kratimenos

Koutroulis

Agarwal

et al. 2017

Sci Rep

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We have previously shown that cerebral Hypoxia-ischemia (HI) results in activation of Src kinase in the newborn piglet brain. We investigated the regulatory mechanism by which the pre-apoptotic proteins translocate from mitochondria to the cytosol during HI through the Src kinase. Newborn piglets were divided into 3 groups (n = 5/group): normoxic (Nx), HI and HI pre-treated with Src kinase inhibitor PP2 (PP2 + HI). Brain tissue HI was verified by neuropathological analysis and by Adenosine Triphosphate (ATP) and Phosphocreatine (PCr) levels. We used western blots, immunohistochemistry, H&E and biochemical enzyme assays to determine the role of Src kinase on mitochondrial membrane apoptotic protein trafficking. HI resulted in decreased ATP and PCr levels, neuropathological changes and increased levels of cytochrome c, Smac/DIABLO and AIF in the cytosol while their levels were decreased in mitochondria compared to Nx. PP2 decreased the cytosolic levels of pre-apoptotic proteins, attenuated the neuropathological changes and apoptosis and decreased the HI-induced increased activity of caspase-3. Our data suggest that Src kinase may represent a potential target that could interrupt the enzymatic activation of the caspase dependent cell death pathway.

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Injury and Repair in the Immature Brain

Cited by 4 publications

References 15 publications

G-CSF attenuates neuroinflammation and stabilizes the blood–brain barrier via the PI3K/Akt/GSK-3β signaling pathway following neonatal hypoxia-ischemia in rats

G-CSF attenuates neuroinflammation and stabilizes the blood–brain barrier via the PI3K/Akt/GSK-3β signaling pathway following neonatal hypoxia-ischemia in rats

Neonatal Brain Hemorrhage (NBH) of Prematurity: Translational Mechanisms of the Vascular-Neural Network

Effect of Src Kinase inhibition on Cytochrome c, Smac/DIABLO and Apoptosis Inducing Factor (AIF) Following Cerebral Hypoxia-Ischemia in Newborn Piglets

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