Combination treatment of r-tPA and an optimized human apyrase reduces mortality rate and hemorrhagic transformation 6 h after ischemic stroke in aged female rats

Abstract

Recombinant tissue plasminogen activator (r-tPA) is the only FDA-approved drug treatment for ischemic stroke and must be used within 4.5h. Thrombolytic treatment with r-tPA has deleterious effects on the neurovascular unit that substantially increases the risk of intracerebral hemorrhage if administered too late. These therapeutic shortcomings necessitate additional investigation into agents that can extend the therapeutic window for safe use of thrombolytics. In this study, combination of r-tPA and APT102, a novel form of human apyrase/ADPase, was investigated in a clinically-relevant aged-female rat embolic ischemic stroke model. We propose that successfully extending the therapeutic window of r-tPA administration would represent a significant advance in the treatment of ischemic stroke due to a significant increase in the number of patients eligible for treatment. Results of our study showed significantly reduced mortality from 47% with r-tPA alone to 16% with co-administration of APT102 and r-tPA. Co-administration decreased cortical (47±5% vs. 29±5%), striatal (50±2%, vs. 40±3%) and total (48±3%vs. 33±4%) hemispheric infarct volume compared to r-tPA alone. APT102 improved neurological outcome (8.9±0.6, vs. 6.8±0.8) and decreased hemoglobin extravasation in cortical tissue (1.9±0.1mg/dl vs. 1.4±0.1mg/dl) striatal tissue (2.1±0.3mg/dl vs. 1.4±0.1mg/dl) and whole brain tissue (2.0±0.2mg/dl vs. 1.4±0.1mg/dl). These data suggest that APT102 can safely extend the therapeutic window for r-tPA mediated reperfusion to 6h following experimental stroke without increased hemorrhagic transformation. APT102 offers to be a viable adjunct therapeutic option to increase the number of clinical patients eligible for thrombolytic treatment after ischemic stroke.