Oxidative stress generated during cerebral ischemia and reperfusion is a critical event leading to bloodbrain barrier (BBB) disruption, with secondary vasogenic edema and hemorrhagic transformation of infarcted brain tissue, restricting the benefit of tissue reperfusion with thrombolytic agents. We have demonstrated that mild cerebral ischemia (30 minutes) in mice deficient in manganese-superoxide dismutase (SOD2-/+) caused delayed (>24 hours) BBB breakdown associated with activation of matrix metalloproteinase (MMP), inflammation, and high brain hemorrhage rates. Our preliminary studies have further shown that overexpression of endothelial NADPH oxidase is associated with the formation of hemorrhagic transformation and intracerebral hemorrhage (ICH) in the SOD2 -/+ mice, and that inhibition of NADPH oxidase significantly reduces ICH and infarct volume. We now hypothesize that activation of endothelial NADPH oxidase and expression of extracellular signal-regulated kinase (ERK) 1/2 signaling cause neurovascular dysfunction, BBB disruption, and endothelial cell death by activation of MMP-9.
Our aim i s to test this hypothesis using this newly developed model of SOD2-/+ mice with delayed BBB disruption. We believe these are novel studies that will provide insights into therapeutic opportunities to minimize oxidative stress-associated hemorrhagic transformation in patients who suffer acute ischemic stroke.
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