Abstract 169: Human Dose tPA Improves Functional Outcomes in Both Sexes in Embolic Model of Stroke: Differential Effect on Hemorrhagic Transformation

Abstract

Tissue plasminogen activator (tPA) is the only FDA-approved therapeutic agent for the treatment of acute ischemic stroke. The widespread use of tPA is still limited by the fear of hemorrhagic transformation (HT) and underlying mechanisms are actively being pursued in preclinical studies. However, experimental models use a 10 times higher dose of tPA than the clinical dose (10 mg/kg) and mostly employ only male animals. In this translational study, we hypothesized that low dose tPA would achieve clot lysis, decrease neurovascular injury and improve functional outcomes in both sexes. Aged-matched male and female Wistar rats (n=5-7) have been treated with or without tPA (1 mg/kg, i.v.) at 90 min after embolic middle cerebral artery occlusion with a fibrin-rich humanized clot. The neurological deficiency (Bederson score and adhesive removal test -ART), infarct size, HT index, and edema ratio were assessed 3 days after surgery (Table). Compared to male rats, female rats had smaller infarct size and better functional outcomes as previously reported in the literature. tPA decreased infarct size in both sexes. tPA reduced edema in males with no effect in females. While there was no difference in HT between males and females without tPA, HT was less in the female + tPA group. Functional outcomes, especially ART, were significantly improved with tPA in both sexes. These data suggest that 1) thrombolysis with a low dose tPA is effective in improving short term outcomes in both sexes, and 2) better functional outcomes in females are further enhanced with tPA. Additional studies are in progress to explore long term effects and the impact of therapeutic window, age and sex steroids on outcomes as well as the underlying mechanisms contributing to less HT in females.