Perivascular astrocyte swelling after BBB disruption

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 DESCRIPTION (provided by applicant): There is marked swelling of perivascular endfeet after cerebral ischemia. This has been thought to result from parenchymal injury. However, our preliminary studies have found that plasma and serum both cause marked rapid astrocyte swelling in vitro, suggesting that ischemia-induced blood-brain barrier (BBB) disruption and an entry of plasma constituents may contribute to astrocyte swelling. In normal brain, there is a marked L-glutamate and L-aspartate gradient between plasma and brain extracellular space, with plasma concentrations being ~10 fold higher. These excitatory amino acids can cause astrocyte swelling, an effect blocked by excitatory amino acid transport (EAAT1/2 mediated) inhibition. Such inhibition also reduces serum-induced astrocyte swelling, suggesting that an influx of these excitatory amino acids from blood after BBB disruption may contribute to astrocyte swelling. The aim of this proposal is to extend these findings in vivo and to examine whether serum/plasma-induced astrocyte swelling may form a cuff that limits the occurrence of hemorrhage after BBB disruption but which may also contribute to brain edema formation. In particular, we will: 1) examine whether BBB disruption without ischemia causes endfeet swelling and whether this can be blocked by an EAAT1/2 inhibitor; and 2) determine whether there is swelling of perihematomal astrocytes after intracerebral hemorrhage (ICH) which forms a perihematomal cuff and whether blocking astrocyte swelling with a EAAT1/2 inhibitor prevents cuff formation increasing hematoma size but limiting ICH-induced edema formation. A greater understanding of astrocyte endfeet swelling after BBB disruption and ischemic/ hemorrhagic stroke may provide insights into how to treat brain edema and limit cerebral hemorrhage (hematoma expansion). In addition, these results may be of importance to the many other neurological conditions associated with BBB dysfunction.