Potential role of Daprodustat for neuroprotection in an in vitro ischaemic stroke model (360G-Wellcome-211970_Z_18_Z)

Ischaemic tolerance induced by pre and postconditioning is a promising endogenous mechanism of brain ischaemia protection, illustrating an ability to prevent or reverse neuronal injuries in ischaemic stroke. The neuroprotection is associated with hypoxia-inducible factors (HIFs), which are master regulators of the hypoxia/ischaemia response in cells. The presence of HIF in cells is tightly controlled by HIF prolyl hydroxylases (PHD). It has been proposed that modulation of HIF-PHD activity is of potential therapeutic use in ischaemic stroke, owing to the direct connection between oxygenase-dependent catalysis and the physiological response to hypoxia. The inhibition of HIF-PHD not only exerts pleiotropic neuroprotective effects as a consequence of HIF induction but also has anti-oxidant and anti-inflammation effects. HIF-PHD inhibition engages multiple downstream effector pathways indicating it can challenge the heterogeneity in stroke pathophysiology present in humans. The proposed study will investigate the potential role of Daprodustat, a selective PHD inhibitor, on ischaemic neuroprotection, and elucidate the molecules involved in the protective effect of HIF-PHD inhibition. The project outcomes will aid the development of small molecule HIF PHD inhibitors, which can activate brain endogenous adaptive programs and address the complexity inherent in cerebral ischaemia pathophysiology. Keywords: neuroprotection, ischaemia, stroke, HIF, PHD, daprodustat