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GSK3β inhibition pr...
GSK3β inhibition protects the immature brain from hypoxic-ischaemic insult via reduced STAT3 signalling
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- D'angelo, Barbara (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology
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- Ek, C. Joakim (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi,Institute of Neuroscience and Physiology
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- Sun, Yanyan (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för klinisk neurovetenskap och rehabilitering,Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation
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- Zhu, Changlian, 1964 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för klinisk neurovetenskap och rehabilitering,Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation
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- Sandberg, Mats, 1953 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine
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- Mallard, Carina, 1963 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology
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(creator_code:org_t)
- Elsevier BV, 2016
- 2016
- Engelska.
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Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908. ; 101, s. 13-23
- Relaterad länk:
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https://europepmc.or...
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Hypoxic-ischaemic (HI) injury is an important cause of neurological morbidity in neonates. HI leads to pathophysiological responses, including inflammation and oxidative stress that culminate in cell death. Activation of glycogen synthase kinase 3β (GSK3β) and the signal transducer and activator of transcription (STAT3) promotes brain inflammation. The purpose of this study was to test whether inhibition of GSK3β signalling protects against neonatal HI brain injury. Mice were subjected to HI at postnatal day (PND) 9 and treated with a selective GSK3β inhibitor, SB216763. Brain injury and caspase-3 activation, anti-oxidant and inflammatory mRNA responses and activation of STAT3 were analysed. Our results show that HI reduced phosphorylation of GSK3β, thus promoting its kinase activity. The GSK3β inhibitor reduced caspase-3 activation and neuronal cell death elicited by HI and reverted the effects of HI on gene expression of the anti-oxidant enzyme sod2 and mitochondrial factor pgc1α. The HI insult activated STAT3 in glial cells and GSK3β inhibition attenuated STAT3 phosphorylation and its nuclear translocation following HI. Further, GSK3β inhibition reduced HI-induced gene expression of pro-inflammatory cytokines tnfα and Il-6, while promoted the anti-inflammatory factor Il-10. In summary, data show that GSK3β inhibition is neuroprotective in neonatal HI brain injury likely via reduced pro-inflammatory responses by blocking STAT3 signalling. Our study suggests that pharmacological interventions built upon GSK3β silencing strategies could represent a novel therapy in neonatal brain injury. © 2015 Elsevier Ltd. All rights reserved.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Physiology (hsv//eng)
Nyckelord
- GSK3β
- Hypoxia-ischaemia
- Neuroinflammation
- Oxidative stress
- Perinatal
- STAT3
- 2 (2
- 4 dichlorophenyl) 3 (1 methyl 3 indolyl)maleimide
- caspase 3
- glycogen synthase kinase 3beta
- interleukin 10
- interleukin 6
- STAT3 protein
- tumor necrosis factor alpha
- animal cell
- animal experiment
- animal model
- animal tissue
- antioxidant activity
- apoptosis
- Article
- brain blood flow
- brain hypoxia
- brain infarction size
- cell death
- cell fractionation
- cell loss
- cell proliferation
- cell survival
- controlled study
- cytokine release
- encephalitis
- enzyme activation
- enzyme inhibition
- gene
- gene expression
- gene translocation
- glia cell
- Il 10 gene
- Il 6 gene
- mouse
- nerve cell
- neuroprotection
- newborn
- nonhuman
- pgc1alpha gene
- priority journal
- protein phosphorylation
- signal transduction
- sod2 gene
- tnfalpha gene
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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