title: Inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) reduces neonatal hypoxic-ischaemic brain damage.
abstract: Hypoxic-ischaemic encephalopathy is a leading cause of child death, with high mortality and morbidity, including cerebral palsy, epilepsy and cognitive disabilities. Hypoxia-ischaemia (HI) strongly up-regulates Signal Transducer and Activator of Transcription 3 (STAT3) in the immature brain. Our aim was to establish whether STAT3 up-regulation is associated with neonatal HI-brain damage and evaluate the phosphorylated STAT3-contribution from different cell types in eliciting damage. We subjected postnatal day seven mice to unilateral carotid artery ligation followed by 60 min hypoxia. Neuronal STAT3-deletion reduced cell death, tissue loss, microglial and astroglial activation in all brain regions. Astroglia-specific STAT3-deletion also reduced cell death, tissue loss and microglial activation, although not as strongly as the deletion in neurons. Systemic pre-insult STAT3-blockade at tyrosine 705 (Y705) with JAK2-inhibitor WP1066 reduced microglial and astroglial activation to a more moderate degree, but in a pattern similar to the one produced by the cell-specific deletions. Our results suggest that STAT3 is a crucial factor in neonatal HI-brain damage and its removal in neurons or astrocytes, and, to some extent, inhibition of its phosphorylation via JAK2-blockade reduces inflammation and tissue loss. Overall, the protective effects of STAT3 inactivation make it a possible target for a therapeutic strategy in neonatal HI. Current data show that neuronal and astroglial STAT3 molecules are involved in the pathways underlying cell death, tissue loss and gliosis following neonatal hypoxia-ischaemia, but differ with respect to the target of their effect. Y705-phosphorylation contributes to hypoxic-ischaemic histopathology. Protective effects of STAT3 inactivation make it a possible target for a therapeutic strategy in neonatal hypoxia-ischaemia.
authors.affiliation: UCL Institute for Women's Health, Maternal & Fetal Medicine, Perinatal Brain Repair Group, London WC1E 6HX, UK.
authors.forename: Mariya
authors.initials: M
authors.lastname: Hristova
authors.affiliation: UCL Institute for Women's Health, Maternal & Fetal Medicine, Perinatal Brain Repair Group, London WC1E 6HX, UK.
authors.forename: Eridan
authors.initials: E
authors.lastname: Rocha-Ferreira
authors.affiliation: Cell Growth and Regeneration Lab, MRC Laboratory for Molecular Cell Biology, University College London, WC1E 6BT, UK.
authors.forename: Xavier
authors.initials: X
authors.lastname: Fontana
authors.affiliation: UCL Institute for Women's Health, Maternal & Fetal Medicine, Perinatal Brain Repair Group, London WC1E 6HX, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Thei
authors.affiliation: UCL Institute for Women's Health, Maternal & Fetal Medicine, Perinatal Brain Repair Group, London WC1E 6HX, UK.
authors.forename: Rheanan
authors.initials: R
authors.lastname: Buckle
authors.affiliation: UCL Institute for Women's Health, Maternal & Fetal Medicine, Perinatal Brain Repair Group, London WC1E 6HX, UK.
authors.forename: Melina
authors.initials: M
authors.lastname: Christou
authors.affiliation: UCL Institute for Women's Health, Maternal & Fetal Medicine, Perinatal Brain Repair Group, London WC1E 6HX, UK.
authors.forename: Supanida
authors.initials: S
authors.lastname: Hompoonsup
authors.affiliation: UCL Institute for Women's Health, Maternal & Fetal Medicine, Perinatal Brain Repair Group, London WC1E 6HX, UK.
authors.forename: Naomi
authors.initials: N
authors.lastname: Gostelow
authors.affiliation: UCL Institute for Women's Health, Maternal & Fetal Medicine, Perinatal Brain Repair Group, London WC1E 6HX, UK.
authors.forename: Gennadij
authors.initials: G
authors.lastname: Raivich
authors.affiliation: UCL Institute for Women's Health, Maternal & Fetal Medicine, Perinatal Brain Repair Group, London WC1E 6HX, UK.
authors.forename: Donald
authors.initials: D
authors.lastname: Peebles
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D000860:Hypoxia / Q000378:metabolism*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse
keywords: STAT3; astroglia; microglia; neonatal hypoxia-ischaemia; neuroprotection