Abstract WMP84: Effects of a New Thrombolytic Compound DC007d in Acute Brain Tissue Damage After Focal Embolic Stroke in Rats

Abstract

Background and Purpose: DC007D is a novel small molecule designed to have thrombolytic and free radical scavenging activities. In this study, we aimed to test the potential neuroprotective effects of DC007D in embolic clot model of focal ischemic stroke in rats. Methods: All animals received intravenous infusion of either saline, 10 mg/kg DC007D or 10 mg/kg tPA at each experimental time point (1.5, 3 and 4.5 hrs after stroke, respectively). In first set of experiments, animals were treated at 1.5-hr after stroke. We performed a time course of multi-parametric MRI analysis including perfusion, diffusion and T2 relaxation. Brain infarction size and swelling rate were measured by TTC staining at 24 hrs after stroke. Next, in 3- and 4.5-hrs treatment experiments, we examined acute brain infarct volume, brain swelling rate, hemorrhagic transformation, neurological deficits. Additionally, we also tested potentially direct neuroprotection effects of DC007D in a mechanical filament pMCAO rat model. Lastly, the effect of DC007D in tPA activity in vitro, INR, and serum levels of tPA and PAI-1 activities in vivo at 24 hrs after stroke were assessed and compared. Results: Both tPA and DC007D treated at 1.5 hrs after stroke reduced hypoperfused area, diffusion, T2 lesion size and TTC-stained infarction. When treated at 3 hrs after stroke, DC007D had significantly better therapeutic effects in reducing brain infarction size, swelling rate and hemorrhagic transformation compared to conventional tPA treatment group. When treated at 4.5 hrs after stroke, both tPA and DC007D had no effects in brain infarction. However, tPA, but not DC007D, significantly increased brain swelling and intracerebral hemorrhagic transformation compared to saline controls. Our experimental results also showed that DC007D failed to have direct neuroprotection in the mechanical pMCAO rat model. Lastly, DC007D did not interfere tPA activity in vitro, and also did not significantly alter INR, serum levels of tPA and PAI-1 activities post stroke in vivo. Conclusions: DC007D is neuroprotective to embolic focal stroke of rats, likely via tPA/PAI-1 activity independent thrombolytic mechanism. It might be developed as a new and novel thrombolytics or adjunct for tPA thrombolytic reperfusion therapy.