Blood brain barrier breakdown is a common element in many neurological diseases; an extensive literature demonstrates temporal and/or spatial associations between the inflammatory processes that underly blood brain barrier breakdown and subsequent death of neural tissue (PAS-04-072). Further, recent longitudinal neuro-imaging studies in stroke patients indicate that early post-ischemic blood brain barrier breakdown correlates with an increased likelihood for hemorrhagic transformation and poor clinical outcome (Latour et al, Ann Neurol, 2004, in press). However, the temporal and spatial patterns of blood brain barrier break down are poorly characterized, and the underlying mechanisms that trigger these processes remain poorly understood. We propose to develop a new experimental method to quantify blood brain barrier breakdown after experimental stroke in the adult rat. The major goal of these studies is to develop quantitative methods to measure blood brain barrier breakdown and also preserve tissue morphology for correlative and quantitative immunocytochemical studies of tissue hypoxia, thrombosis and low blood flow. In this R21 developmental project, we will use a rat stroke model of reversible middle cerebral artery occlusion (MCAo) to develop measures of ischemic heterogeneity and test potential mechanisms underlying that heterogeneity. 1. Develop methods for the quantitation of local microvascular blood brain barrier break down. 2. Validate that areas of FITC-dextran blood brain barrier breakdown correlate with ischemic pathology by co-staining for markers of tissue hypoxia, vessel reactivity, and mircrothrombosis. 3. Validate that FITC-dextran blood brain barrier breakdown correlates with in vivo measures of low blood flow in microvessels.
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