Neuroprotective Strategies for Acute Ischemic Stroke: Targeting Oxidative Stress and Prolyl Hydroxylase Domain Inhibition in Synaptic Signalling.

• Acute ischemic stroke is the primary reason for sustained disability and the second leading cause of death worldwide. • PHD inhibitors have neuroprotective activity in stroke models through the induction of the PHD/HIF defence mechanism. • Modulation of ROS production or degradation improves neuronal viability against ischemia-reperfusion injury. • Treatment with antioxidant compounds restores the cellular redox conditions and rescues synaptic potentiation failure after the ischemic insult. • PHD inhibitors can modulate hippocampal synaptic plasticity possibly through a HIF-independent pathway. Acute ischemic stroke (AIS) is the primary reason for sustained disability and the second leading cause of death worldwide. Multiple complex mechanisms contribute to the pathophysiology of AIS leading to disruptions in synaptic signalling and plasticity. Two key interrelating features of cerebral ischemia include the reduction in oxygen and glucose availability and oxidative damage. During ischemia, oxygen deprivation causes several adaptive changes including the stabilisation of neuroprotective hypoxia-inducible factors (HIFs). HIF activity is regulated by oxygen-dependent hydroxylases termed prolyl-4-hydroxylase domain enzymes (PHDs) and can be pharmacologically activated with PHD inhibitors. Preconditioning the HIF system with PHD inhibitors in in vitro ischemic models such as oxygen-glucose deprivation (OGD) has demonstrated neuroprotective effects on synaptic transmission and modulatory effects on synaptic plasticity. Restoration of blood flow as quickly as possible remains the gold-standard for all current therapeutic approaches to stroke. However, rapid recanalization is associated with major complications, of which cerebral ischemia-reperfusion injury (I-RI) is one of the most severe. I-RI results in oxidative damage leading to the neurotoxic overproduction of reactive oxygen species. Antioxidant treatments have shown positive effects in-vitro but some of which show modulatory effects on synaptic plasticity. Therefore, a greater knowledge of the exact mechanisms involved in ischemia/aglycemia and oxidative damage during AIS is a priority in order to arrive at a better understanding of how they can be targeted for neuroprotection. This review focuses on the response of neurons to HIF and its targets, including PHD enzymes and preconditioning with PHD inhibitors. We also discuss the modulation of synaptic transmission with antioxidants and how they both contribute to and modulate synaptic plasticity.