title: GSK3β inhibition protects the immature brain from hypoxic-ischaemic insult via reduced STAT3 signalling.
abstract: 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.
authors.affiliation: Institute of Neuroscience and Physiology, Department of Physiology, University of Gothenburg, Sweden.
authors.forename: Barbara
authors.initials: B
authors.lastname: D'Angelo
authors.affiliation: Institute of Neuroscience and Physiology, Department of Physiology, University of Gothenburg, Sweden.
authors.forename: C Joakim
authors.initials: CJ
authors.lastname: Ek
authors.affiliation: Institute of Neuroscience and Physiology, Department of Clinical Neuroscience, University of Gothenburg, Sweden.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Institute of Neuroscience and Physiology, Department of Clinical Neuroscience, University of Gothenburg, Sweden.
authors.forename: Changlian
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Sandberg
authors.affiliation: Institute of Neuroscience and Physiology, Department of Physiology, University of Gothenburg, Sweden. Electronic address: carina.mallard@neuro.gu.se.
authors.forename: Carina
authors.initials: C
authors.lastname: Mallard
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D053148:Caspase 3 / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy*; D007211:Indoles / Q000627:therapeutic use*; D008301:Maleimides / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
chemical_list: D000089622:Doublecortin Domain Proteins; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C417521:SB 216763; D050796:STAT3 Transcription Factor; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3
keywords: GSK3β; Hypoxia-ischaemia; Neuroinflammation; Oxidative stress; Perinatal; STAT3