Comparison of the post-embolization effects of tissue-plasminogen activator and simvastatin on neurological outcome in a clinically relevant rat model of acute ischemic stroke

Abstract

Data has emerged, largely from non-thromboembolic animal models of stroke, that suggests that statins, which have efficacy in preventing strokes when given pre-ischemically, may have a positive effect on stroke even when given post-ischemically, possibly through pleitropic cerebrovascular effects. The goal of this study was to characterize the effects of IV tPA in a clinically relevant model of stroke utilizing a vascular occlusion with a freshly formed clot, and evaluate the effects of post-ischemic administration of simvastatin on stroke outcome in this model. Neurological deficit, clot burden, and lesion volume were assessed after treatment with tPA in one experiment, and after treatment with simvastatin in another. In the tPA experiment, treatment with 10 mg/kg of tPA IV (with 20% given as an initial bolus, and 80% given as an infusion over the remaining 30 min), starting within an hour after stroke, resulted in significant reductions, compared with control animals, in neurological deficit (mean ± SD neuroscores of 21.5 ± 21.1 and 30 ± 29.3, respectively, p = 0.005), clot burden ( p = 0.010) and lesion volume ( p = 0.049) at 24 h. In the simvastatin experiment on the other hand, treatment with a 20 mg/kg of simvastatin as a single intraperitoneal dose within an hour after stroke resulted in no salutary effects on neurological deficit, clot burden or lesion volume compared with controls at 24 h. These results suggest that more research needs to be done to fully ascertain the therapeutic potential and optimal dosing paradigm of a post-ischemic treatment with a statin.