GSK3β inhibition protects the immature brain from hypoxic-ischaemic insult via reduced STAT3 signalling

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MARC

D'angelo, BarbaraGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology (author)

GSK3β inhibition protects the immature brain from hypoxic-ischaemic insult via reduced STAT3 signalling

Article/chapterEnglish2016

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Elsevier BV,2016

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LIBRIS-ID:oai:gup.ub.gu.se/226637
https://gup.ub.gu.se/publication/226637URI
https://doi.org/10.1016/j.neuropharm.2015.09.017DOI

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Language:English

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

Notes

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.

Subject headings and genre

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
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

Added entries (persons, corporate bodies, meetings, titles ...)

Ek, C. JoakimGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi,Institute of Neuroscience and Physiology(Swepub:gu)xekjom (author)
Sun, YanyanGothenburg 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(Swepub:gu)xsunyg (author)
Zhu, Changlian,1964Gothenburg 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(Swepub:gu)xzhuch (author)
Sandberg, Mats,1953Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine(Swepub:gu)xsamat (author)
Mallard, Carina,1963Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology(Swepub:gu)xmallc (author)
Göteborgs universitetInstitutionen för neurovetenskap och fysiologi, sektionen för fysiologi (creator_code:org_t)

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In:Neuropharmacology: Elsevier BV101, s. 13-230028-3908

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