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Inhibition of Signal Transducer and Activator of Transcription 3 ( STAT 3) reduces neonatal hypoxic‐ischaemic brain damage
Author(s) -
Hristova Mariya,
RochaFerreira Eridan,
Fontana Xavier,
Thei Laura,
Buckle Rheanan,
Christou Melina,
Hompoonsup Supanida,
Gostelow Naomi,
Raivich Gennadij,
Peebles Donald
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13490
Subject(s) - stat3 , gliosis , stat protein , microglia , brain damage , hypoxia (environmental) , programmed cell death , biology , ischemia , medicine , neuroscience , microbiology and biotechnology , inflammation , phosphorylation , immunology , chemistry , apoptosis , biochemistry , organic chemistry , oxygen
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 ( STAT 3) in the immature brain. Our aim was to establish whether STAT 3 up‐regulation is associated with neonatal HI ‐brain damage and evaluate the phosphorylated STAT 3‐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 STAT 3‐deletion reduced cell death, tissue loss, microglial and astroglial activation in all brain regions. Astroglia‐specific STAT 3‐deletion also reduced cell death, tissue loss and microglial activation, although not as strongly as the deletion in neurons. Systemic pre‐insult STAT 3‐blockade at tyrosine 705 (Y705) with JAK 2‐inhibitor WP 1066 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 STAT 3 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 JAK 2‐blockade reduces inflammation and tissue loss. Overall, the protective effects of STAT 3 inactivation make it a possible target for a therapeutic strategy in neonatal HI .Current data show that neuronal and astroglial STAT 3 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 STAT 3 inactivation make it a possible target for a therapeutic strategy in neonatal hypoxia‐ischaemia.