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Signal transduction and activation of transcription factor 3 (STAT3) mediates neonate hypoxic ischaemic brain injury
  1. M Hristova1,
  2. L Thei1,
  3. N Gostelow1,
  4. D Peebles1,
  5. A Behrens2,
  6. S Akira3,
  7. G Raivich1
  1. 1Perinatal Brain Repair Group, Institute for Women's Health, University College London, London, UK
  2. 2Mammalian Genetics Laboratory, Cancer Research UK, London, UK
  3. 3Institute for Molecular and Cellular Biology, Osaka University, Osaka, Japan


Hypoxia-ischaemia (HI) is a major cause of neonatal brain injury. Although a number of biochemical cascades have been implicated, the downstream targets, at the level of transcriptional regulation still remain unclear. The signal transduction and activator of transcription factor 3 (STAT3) is strongly upregulated following peripheral and central trauma and thus a possible candidate. In the current study, we investigated the regulation and functional role of STAT3 in the neonatal HI brain injury in the Rice-Vannucci model in postnatal day 7 mice, using 30 (mild) or 60 min (severe) exposure to 8% Oxygen and assessment of outcome based on size of infarct (Nissl), extent of cell death (TUNEL density) and microglial activation (alphaM&X levels).

On immunohistochemical level, HI insult resulted in transient upregulation of phosphorylated STAT3 (Y705) in cortical, hippocampal and thalamic neurons, with a peak at 2–4 h after insult. Moreover, cell-type specific deletion of STAT3 in neurons using Synapsin:Cre in homozygous STAT3-flox mutant mice (n=5) resulted in a significant and strong reduction of tissue damage (−80%, p<5% t-test) in hippocampus, cortex, striatum and thalamus following the severe, 60 min insult, compared with their STAT3+ littermate controls (n=5). A more moderate effect was also observed in the subcortical white matter. We are currently exploring the results in the milder, 30 min HI, to obtain data on severity-specific sensitivity to STAT3 deletion. Since Y705-phosphorylation plays an important role in STAT3 function, the use of direct kinase inhibitors could serve as a candidate target for therapeutic intervention in neonatal brain damage.

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