Spontaneous intracerebral hemorrhage (ICH) is a common and often fatal stroke subtype. If the patient survives the ictus, the resulting hematoma within the brain parenchyma triggers a series of events leading to secondary insults and severe neurological deficits. Brain edema plays an important role in the secondary brain injury following ICH. It is the long-term goal of our laboratory to identify the mechanisms involved in brain edema formation following ICH. Our previous studies indicate that edema formation following ICH may involve several phases. An early phase involving the clotting cascade and thrombin production. Although our data indicate that thrombin inhibition is a therapeutic target, concerns over rebleeding may limit the utility of this approach. It is, therefore, important to understand the downstream mechanisms activated by thrombin. Our preliminary studies have found: 1) thrombin activity increases immediately after ICH; 2) complement cascade is activated in the brain following ICH and thrombin injection; 3) thrombin upregulates protease-activated receptors (PARs); 4) thrombin increases brain TNF-alpha levels; 5) thrombin potentiates iron-mediated damage. These results lead us to test the following specific aims: 1) To determine whether thrombin formation following ICH activates the complement cascade in the brain resulting in blood-brain barrier disruption and edema formation. These experiments will employ complement inhibitors as well as C3 and C5 deficient mice. 2) To determine whether thrombin causes brain edema through activation of PARs. These experiments will employ PAR-l, 3 and -4 agonists and antagonists as well as PAR-1 knockout mice. 3) To determine whether thrombin exacerbates brain edema induced by iron. The purpose of our project is to investigate the mechanisms involved in thrombin-induced brain edema. If our hypotheses are correct, these experiments may lead to novel methods of treating ICH.
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