102 BB-031 Recanalizes MCAO and Reduces Inflammation in Canine Model of LVO Stroke

Abstract

INTRODUCTION: Acute ischemic stroke (AIS) is the leading cause of long term disability. rtPA treatment of AIS results in intracranial hemorrhage (ICH) in 7% of patients with 40% mortality. Increased matrix metalloprotease-9 (MMP-9) correlates with ICH, while reduced levels maintain integrity of the blood brain barrier (BBB), preventing ICH. Von Willebrand Factor (VWF) induces both thrombosis and inflammation in large vessel occlusion (LVO) stroke. BB-031 targets VWF, and lyses thrombotic occlusion. BB-025 reverses BB-031. METHODS: After 6 hours of autologous canine MCAO, animals were treated with vehicle, BB-031, and BB-031+BB-025. VWF inhibition, TICI scores, and plasma inflammatory markers [VWF, interleukin-1 (IL-1b), interleukin-6 (IL-6), tumor necrosis factor-a (TNF- a), and matrix metalloproteinase-9 (MMP-9)] were analyzed over the course of the study. RESULTS: Within 15 minutes of vehicle treatment, VWF increased by 3.102 ± .382 ng/ml (n = 6) whereas BB-031 reduced VWF by 0.223 ± .154 ng/ml (p < 0.05) (n = 8). BB-031-treated animals had TICI > 2B in 62.5% of the animals. Although IL-1b and IL-6 were unchanged, and TNF-a was not detectable, MMP-9 levels were lower in BB-031-treated animals at sacrifice compared to both vehicle and BB-031+BB-025 (p < 0.0001). CONCLUSIONS: BB-031 treatment inhibited VWF, increased reperfusion, and reduced MMP-9 after canine MCAO, suggesting that in addition to recanalization, inhibiting VWF mitigates inflammation and iatrogenic ICH.