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Updated: Mar 28, 2026
The Hypoxic Ischemic Encephalopathy Model of Perinatal Ischemia
Published on: November 19, 2008
Inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) reduces neonatal hypoxic-ischaemic brain
Mariya Hristova1, Eridan Rocha-Ferreira1, Xavier Fontana2
1UCL Institute for Women's Health, Maternal & Fetal Medicine, Perinatal Brain Repair Group, London WC1E 6HX, UK.
Insights
Signal Transducer and Activator of Transcription 3 (STAT3) plays a key role in neonatal hypoxic-ischaemic brain damage. Targeting STAT3 in neurons and astrocytes offers a potential therapeutic strategy to reduce inflammation and tissue loss.
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- Neonatal hypoxic-ischaemic encephalopathy (HIE) is a major cause of child mortality and long-term disability.
- Hypoxia-ischaemia (HI) significantly increases Signal Transducer and Activator of Transcription 3 (STAT3) expression in the developing brain.
Purpose of the Study:
- To investigate the association between STAT3 up-regulation and neonatal HI brain damage.
- To determine the contribution of phosphorylated STAT3 from different cell types to brain injury.
Main Methods:
- Postnatal day seven mice underwent unilateral carotid artery ligation followed by hypoxia.
- Neuronal and astroglia-specific STAT3 deletions were performed.
- Systemic STAT3 phosphorylation blockade using a JAK2 inhibitor (WP1066) was administered.
Main Results:
- Neuronal STAT3 deletion significantly reduced cell death, tissue loss, and glial activation.
- Astroglia-specific STAT3 deletion also decreased these markers, though to a lesser extent.
- JAK2 inhibition partially reduced glial activation, mirroring effects of STAT3 deletion.
Conclusions:
- STAT3 is a critical mediator of neonatal HI brain injury.
- Targeting STAT3 in neurons and astrocytes demonstrates protective effects against HI-induced damage.
- STAT3 inactivation presents a potential therapeutic avenue for neonatal hypoxic-ischaemic encephalopathy.
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.
