Abstract 3983: Decreased Brain Swelling, Stroke- and Blood-Brain Barrier-lesion Volumes after Combination Treatment with Simvastatin and Tissue Plasminogen Activator in a Rat model of Embolic Stroke

Background and Purpose - Cytotoxic and vasogenic edema in acute stroke may lead to brain swelling. Acute treatment with tissue plasminogen activator (TPA) can increase blood-brain barrier (BBB) damage and vasogenic edema. Using a rat embolic stroke model, this study investigated the efficacy of simvastatin in combination with TPA to reduce brain swelling. Methods - One middle cerebral artery in young adult male Wistar rats (300 g) was embolized with a day-old fibrin-rich blood clot. The rats were divided randomly into 6 groups (N=6-8 per set): 1) Control; 2) Simvastatin (20 mg/kg; subcutaneous) at 30 min and at 24 h post-ictus; 3) TPA (10 mg/kg; intravenous) at 2 h post-ictus; 4) TPA at 3 h post-ictus; 5) Simvastatin plus TPA at 2 h; and 6) Simvastatin plus TPA at 3 h. They were injected with [ 14 C]α-aminoisobutyric acid and the brains processed for Nissl histology and quantitative autoradiography (QAR) at 48 h. Brain hemispheric and stroke lesion volumes from Nissl-stained brain sections and BBB lesion volumes from QAR images were measured using an image analysis system. Data were expressed as mean ± standard deviation of the ratios to the contralateral hemisphere volumes. They were analyzed by Student’s t-tests and significance inferred at P <0.05 (*). Results - Compared to controls, simvastatin and TPA treatments alone, combination treatment at both 2 and 3 h post-ictus was effective in reducing brain swelling, stroke- and BBB-lesion volumes ( Figure ). Treatment at 2 h post-ictus seemed to be more effective than at 3 h. Conclusions - These data suggest that simvastatin in combination with TPA may attenuate brain swelling in acute stroke and, thus, may be a viable adjuvant agent with TPA. Edema fluid formation and consequent brain swelling influnce the disease outcome and, moreover, can even be fatal. Therefore, efficacy and mechanisms of action of simvastatin in controlling them in stroke and other acute brain trauma deserve further investigation.