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.

Inhibition of miR‐337‐3p involved in the protection of CoCl2‐induced injury in PC12 cells via activating JAK2/STAT3 signaling pathway

“…Previous study demonstrated the activation of JAK2/STAT3 signaling pathway can decrease the number of apoptotic cells and the volume of cerebral infarction following the attack to protect the brain tissues . Domenico et al also supported the notion that STAT3 has the neuroprotective effect in temporary cerebral ischemia by affecting the gene transcription, synaptic transmission, cell structure, and metabolism, suggesting the involvement of the JAK2/STAT3 signaling pathway in the hypoxic encephalopathy . Notably, hypoxia could affect the expressions of multiple microRNAs (miRNAs), which is a group of single‐chain, noncoding, and short RNA in length of about 18 to 25 nucleotides, with high conservation in different species .…”

“…8 Domenico et al also supported the notion that STAT3 has the neuroprotective effect in temporary cerebral ischemia by affecting the gene transcription, synaptic transmission, cell structure, and metabolism, 9 suggesting the involvement of the JAK2/STAT3 signaling pathway in the hypoxic encephalopathy. 10,11 Notably, hypoxia could affect the expressions of multiple microRNAs (miRNAs), which is a group of single-chain, noncoding, and short RNA in length of about 18 to 25 nucleotides, with high conservation in different species. 12 For example, hypoxia increased the expression levels of miR-204 in PC12 cells, 2 whereas miR-210 overexpression could protect PC-12 cells from hypoxia-induced injuries.…”

Questions and (some) answers on reactive astrocytes

“…Indeed, even reactive astrocytes activated by the same pathway can have different effects on specific disease outcomes. STAT3 signaling in reactive astrocytes has detrimental effects in mouse models of AD (Ceyzériat et al, ; Reichenbach et al, ), or hypoxia (Hristova et al, ), no significant effect in the context of acute mitochondria toxicity (O'Callaghan et al, ) but has beneficial effects in neonatal white matter injury (Nobuta et al, ), after SCI, by promoting glial scar formation (Anderson et al, ; Herrmann et al, ; Okada et al, ), and in HD models, by reducing mutant Huntingtin aggregation (Ben Haim, Ceyzeriat, et al, ). Intriguingly, a recent study by Tyzack et al () suggested that the upstream activator (IL6 or EphB1‐ephrine‐B1 signaling) controls the final molecular profile induced by STAT3 in reactive astrocytes (Table ).…”

Neuroprotective actions of taurine on hypoxic-ischemic brain damage in neonatal rats

“…Statistics suggests that approximately 40% of the affected infants die in the neonatal period and an additional 30% have lifelong neurological deficits including cerebral palsy, epilepsy and cognitive disabilities (Hristova et al, 2016). The treatment and care for the sequelae of HIBD require extensive resources.…”