Abstract W P244: Inhibition of Matrix Metalloprotease 3 Reduces Vascular Injury and Improves Functional Outcomes in Hyperglycemic Stroke

Abstract

Matrix metalloprotease 3 (MMP3) is a zinc endopeptidase that has a broad substrate specificity and can cause degradation of basal lamina and tight junction proteins of the blood brain barrier. MMP3 plays a critical role in mediating the tPA induced hemorrhagic transformation (HT) after stroke. We have previously shown that increased MMP3 activity was associated with greater vascular injury in hyperglycemic stroke. Thus, this study tested the hypothesis that MMP3 inhibition reduces the vascular injury and improves the functional outcomes in hyperglycemic stroke. Methods: Control and mildly HG rats (140-200 mg/dl, achieved by 30% glucose injection (IP) 15 min prior to surgery, n=7-9/group) were subjected to 90 min middle cerebral artery occlusion and 24 h reperfusion. In an additional group of HG rats, MMP3 inhibitor (UK 356618, Tocris Bioscience) was IV injected (15 mg/kg) at reperfusion. At 24 h, neurological deficit, infarct size, edema and HT occurrence rate (HT index) were measured. MMP3 activity in isolated cerebrovasculature and brain homogenates was quantified by FRET assay. In addition, MMP3 activity was measured in brain microvascular endothelial cells (BVEC) treated with tPA and subjected to 90 minutes hypoxia/24 h reoxygenation under normal and high glucose conditions. Results: MMP3 significantly reduced the vascular injury (HT index and edema) with no effect on infarct size and this was associated by improved functional outcomes (Table). tPA has significantly increased MMP3 activity in BVEC under either normal or high glucose conditions (*p<0.05 vs control). Conclusion: Our findings that MMP3 inhibition reduces vascular injury and improves functional outcomes identifies MMP3 as a potential therapeutic target in hyperglycemic stroke.