The blood-brain (BBB), whose hallmark is its impermeability, is formed by the brain microvascular endothelium. With the occurrence of a noxious stimulus, activated endothelial cells produce reactive oxygen species (ROS) and release inflammatory mediators. Accumulating evidence suggests that ROS can alter BB permeability and induce cerebral edema and tissue damage, and that the cerebral microvasculature and inflammatory cells are critically involved in this oxidative stress-mediated process. ROS such as superoxide anion are involved in the initiation of immediate cell damage during brain ischemia and injury, as well as in the modulation of cellular signaling and control of gene expression. Thus, antioxidant enzymes that control ROS production possess the ability to effectively modulate the development of brain damage after an insult. The successful development of genetically manipulated mice deficient in or over-expressing the constitutively expressed cytosolic antioxidant, copper/zinc-superoxide dismutase (SOD1), or the inducible mitochondrial antioxidant, manganese-SOD (SOD2), offers a unique opportunity to elucidate, in a molecular fashion, the oxidative mechanisms in brain injury following stroke and mitochondria-related BB dysfunction. Using SOD1- and SOD2-knock-out mutant mice, in addition to SOD1-over-expressors (transgenic[Tg]) and the recently developed SOD2 Tg mice, we will explore the molecular basis of endothelial cell function and injury in the central nervous system. Additionally, we will examine the relationship between mitochondrial dysfunction and microvascular permeability, and the contribution of ROS-induced BBB damage by inflammatory cells. To that end, we will use both in vivo models (transient focal cerebral ischemia and 3-nitroproprionic acid [3-NP-]-induced mitochondrial excitotoxicity) and in vitro (cell culture and microvessel isolation) systems. We believe these are unique and fresh approaches that will provide insights into the oxidative mechanisms of mitochondrial dysfunction that underlies cerebrovascular endothelial cell death/survival in transient focal cerebral ischemia and in 3-NP-induced striatal injury.
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