Oxidative stress generated during cerebral ischemia and reperfusion is a critical event leading to bloodbrainbarrier (BBB) disruption, with secondary vasogenic edema and hemorrhagic transformation of infarctedbrain tissue, restricting the benefit of tissue reperfusion with thrombolytic agents. We have demonstrated thatmild 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 thatoverexpression of endothelial NADPH oxidase is associated with the formation of hemorrhagictransformation and intracerebral hemorrhage (ICH) in the SOD2 -/+ mice, and that inhibition of NADPHoxidase significantly reduces ICH and infarct volume. We now hypothesize that activation of endothelialNADPH oxidase and expression of extracellular signal-regulated kinase (ERK) 1/2 signaling causeneurovascular dysfunction, BBB disruption, and endothelial cell death by activation of MMP-9.
Our aim i s totest this hypothesis using this newly developed model of SOD2-/+ mice with delayed BBB disruption. Webelieve these are novel studies that will provide insights into therapeutic opportunities to minimize oxidativestress-associated hemorrhagic transformation in patients who suffer acute ischemic stroke.
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