Tetorou, Konstantina; (2023) The role of Signal Transducer and Activator of Transcription 3 (STAT3) in neuronal pathways of Neonatal Hypoxic Ischemic Encephalopathy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Hypoxic-ischaemic encephalopathy is a leading cause of child mortality and morbidity. Hypoxia-ischaemia (HI) strongly up-regulates Signal Transducer and Activator of Transcription 3 (STAT3) in the immature brain. There is need for development of alternative therapies for neonatal HI brain damage since the only available treatment therapeutic hypothermia (TH) has rather limited effectiveness and application, especially for infection-sensitised HI cases. We, as well as others, have shown that HI strongly upregulates STAT3 transcription factor in the immature brain and that systemic pharmacological STAT3 inhibition with WP1066 provides short-term neuroprotection. We hypothesised that STAT3 is involved in HI and that two compounds would have therapeutic activity in HI injury: WP1066: a pharmacological Janus Kinase 2 (JAK2) inhibitor of STAT3 and curcumin, a plant-derived compound with anti-inflammatory, antioxidative properties. Furthermore, we hypothesised that microglia-specific TGβR1 deletion, would provide neuroprotection, as it has been described that TGFβ, a pleiotropic cytokine, increases STAT3 phosphorylation. WP1066 potential neuroprotective role was evaluated through intraperitoneal application on a postnatal day 9 neonatal C57Bl/6 HI mouse model, in different doses and time points and demonstrated short- and long-term neuroprotective effects at an optimal dose of 80μg/g body weight. The intraperitoneal administration of curcumin in DMSO solution to postnatal day 9 HI animals showed clear neuroprotection. However, curcumin’s poor bioavailability necessitated further optimisation to make the product suitable for clinical use. Thus, we synthesised curcumin-loaded microspheres P(3HB) and the results showed that intranasal administration after HI is neuroprotective. 4 Additionally, microglial-specific TGFβR-1 deletion provides neuroprotective effect, by increasing the anti-inflammatory microglial levels as assessed with immunofluorescence analysis, thus inducing repair after HI insult. Finally, we established a new infection-sensitised HI model, based on E.coli intravaginal maternal injection. We conclude that both WP1066 and curcumin treatments reduce brain damage after HI insult and could be considered as potential treatment for the condition. Overall, all treatments have an effect on STAT3 phosphorylation, which points towards a detrimental role of STAT3 in HI.

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