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

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 3 beta (GSK3 beta) and the signal transducer and activator of transcription (STAT3) promotes brain inflammation. The purpose of this study was to test whether inhibition of GSK3 beta signalling protects against neonatal HI brain injury. Mice were subjected to HI at postnatal day (PND) 9 and treated with a selective GSK3 beta 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 GSK3 beta, thus promoting its kinase activity. The GSK3 beta 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 pgcl alpha. The HI insult activated STAT3 in glial cells and GSK3 beta inhibition attenuated STAT3 phosphorylation and its nuclear translocation following HI. Further, GSK3 beta inhibition reduced HI-induced gene expression of pro-inflammatory cytokines Wee and Il-6, while promoted the anti-inflammatory factor Il-10. In summary, data show that GSK3 beta 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 GSK3 beta silencing strategies could represent a novel therapy in neonatal brain injury. (C) 2015 Elsevier Ltd. All rights reserved.