Abstract Body: Introduction: Ischemia reperfusion injury (IRI) is a paradoxical and deleterious consequence of current interventions for acute ischemic stroke (AIS). Rapid restoration of oxygen to brain tissue upon reperfusion initiates mitochondrial reverse electron transport (RET) and production of reactive oxygen species (ROS), which exacerbate cell death. A pivotal role of the citric acid cycle intermediate succinate has been identified in driving RET post-reperfusion, whereby succinate accumulated during ischemia is rapidly reoxidized following reperfusion leading to a burst of ROS. Disodium malonate (DSM), a competitive inhibitor of succinate dehydrogenase, has been shown to attenuate RET ROS production following reperfusion and reduce infarct volume in rodent models. Here, we sought to evaluate the effect of DSM on infarct evolution post-reperfusion in a clinically-relevant sheep model of AIS for enhanced clinical translation.

Methods: Male Merino sheep (N=13, 24-36 months, 62±6 kgs) underwent right pterional craniotomy and middle cerebral artery occlusion (MCAo) via aneurysm clip application for 4 hrs followed by reperfusion. Animals were pre-operatively randomized into vehicle (0.9% saline, N=5), medium dose DSM (0.5 mmole/min; N=4) and high dose DSM (1.0 mmole/min; N=4). Treatment was administered via right common carotid catheter at a rate of 15 mL/min for 10 min, starting 5 min prior to reperfusion. MCAo and reperfusion were confirmed on digital subtraction angiography (DSA). One hour following reperfusion, animals underwent magnetic resonance imaging (MRI) with a follow-up MRI performed 6 hours later. Infarct volume was calculated on diffusion weighted imaging (DWI) at each time-point to assess ischemic evolution.

Results: All animals displayed evidence of MCAo and successful reperfusion following aneurysm clip removal (Figure 1). Infarct volume between groups was comparable at 1 hr post reperfusion (P>0.05), however, by 6 hrs infarct expansion was attenuated in animals receiving DSM compared with vehicles (P=0.0037). This was apparent in both the medium (P=0.006) and high (P=0.011) DSM groups.

Conclusions: Intraarterial DSM administration reduces infarct expansion following reperfusion in a sheep model of MCAo. Evaluation of treatment efficacy in a larger cohort of animals is essential to address stroke therapeutic and industry roundtable (STAIR) guidelines and provide evidence to progress DSM to clinical trial for the treatment of IRI in AIS.