Ischemic blood brain barrier: Glial and endothelial cell interactions

Stanford University, Stanford CA

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Abstract

The blood brain barrier (BBB) is necessary to regulate and limit the transport of solutes and proteins into the brain under normal conditions. Under pathological conditions, the BBB can be altered or damaged to permit transmigration of leukocytes and large molecules leading to edema and in the case of complete breakdown, hemorrhage. Such damage is often observed during cerebral ischemia and may result in significant cerebral hemorrhage, a feared complication of thrombolytic therapy. The BBB consists of endothelial cells surrounded by astrocytes and microglia. Following ischemia, reactive oxygen and nitrogen species are generated in the brain by a variety of cell types. These conditions lead to activation of microglia, the brain's resident immune cell. In response to activating stimuli, microglia are capable of expressing inflammatory cytokines, reactive species including superoxide and nitric oxide, and degradative enzymes including matrix metalloproteinases (MMPs). MMPs, once expressed, lead to direct disruption of the BBB resulting in cerebral edema and hemorrhage. We recently observed that microglia potentiate damage to endothelial cells and astrocytes subjected to simulated ischemia. We plan to characterize the mechanisms underlying this observation by examining the effects of simulated ischemia-induced BBB injury as it pertains to 1) the inflammatory cytokines IL-1 beta and TNF-alpha, 2) reactive oxygen and nitrogen species and 3) MMPs. This proposal plans to study these effects both in co-culture models of the BBB and in a whole animal model of hemorrhagic embolic stroke. This work may help identify novel therapeutic targets to reduce brain damage and hemorrhage in the setting of impaired BBB.