Ischaemic stroke is a leading cause of death and disability worldwide. Arising due to arterial occlusion, current treatment involves removing the blockage to rapidly re-establish blood flow to compromised brain tissue, however, this often paradoxically leads to ischaemia reperfusion (I/R) injury.
I/R injury initiates many damaging cellular processes through the production of unstable molecules termed mitochondrial reactive oxygen species (ROS). Previously thought to be a non-specific response, mitochondrial ROS production following reperfusion is now established to arise due to conserved metabolic pathways. Specifically, the accumulation of mitochondrial metabolite succinate has been identified as a key driver in I/R injury, mediating its effects through binding succinate dehydrogenase (SDH).
Malonate, an inhibitor of SDH, has the potential to prevent I/R injury post stroke and markedly improve patient outcomes, with administration leading to a significant reduction in stroke volume in pre-clinical studies. To advance treatment to clinical trial, however, comprehensive evaluation of the efficacy of Malonate administration on stroke volume evolution is required. Neuroimaging is an invaluable tool for the evaluation of I/R clinically, enabling non-invasive assessment of the evolving injury in the same patient following onset of stroke. This project thus seeks to comprehensively evaluate the efficacy of malonate on stroke evolution using neuroimaging tools, specifically magnetic resonance imaging (MRI) and digital subtraction angiography (DSA), in a pre-clinical model of ischaemic stroke. The results of this study aim to support progression of malonate to clinical trial with the ultimate goal to reduce death and disability in ischaemic stroke survivors.