Subarachnoid hemorrhage and intracerebral hemorrhage are important causes of stroke. In spite of the common occurrence of hemorrhage, little is known about how blood and the hemoglobin in blood are metabolized in the CNS, what role hemoglobin might play in mediating injury, and whether there are specific therapeutic approaches that improve outcome from hemorrhage. Hemoglobin contributes to oxidative stress and produces vasospasm when placed around cerebral blood vessels. This proposal will examine the role of the HO-1 and HO-2 hemeoxygenase enzymes in the brain since they are two of the enzymes that metabolize heme in hemoglobin. Subarachnoid injections of whole blood, lysed blood or hemoglobin induce hemeoxygenase-1 (HO-1) in microglia throughout the entire brain. Subarachnoid injections of lysed blood induced the HSP70, HO-1 and HSP47 stress genes in focal regions of rodent brain. The focal regions of heat shock gene injection can be blocked by pre-treatment with anti-oxidant drugs. This proposal will continue to examine experimental subarachnoid hemorrhages produced by injections of lysed blood into the cisterna magna of adult rats or mice. The following series of experiments will test three major hypotheses. (1) Hypothesis: The focal regions of stress gene induction following experimental subarachnoid hemorrhage are ischemic. Experiments: (1) Blood flow, glucose metabolism and the blood brain barrier will be examined in focal regions of stress gene expression following experimental subarachnoid hemorrhage. (2) Hypothesis: HO-1 and HO-2 protect against experimental subarachnoid hemorrhage. Experiments: (2) Focal stress gene expression will be assessed following experimental subarachnoid hemorrhage in HO-1 and HO-2 knockout mice, and following induction of HO-1 with either systemic or subarachnoid injections of pure hemoglobin or stabilized hemin. (3) Hypothesis: Drugs that protect against oxidative stress and ischemic injury block focal regions of stress gene expression following experimental subarachnoid hemorrhage. Experiments: (3) Focal stress gene expression due to subarachnoid hemorrhage will be assessed following treatment with nimodipine, potent anti-oxidants like spin-trap compounds, and following treatment with glutamate receptor antagonists. These studies will help delineate mechanisms of injury following subarachnoid hemorrhage, and will develop a new approach for assessing whether drugs decrease or block injury due to subarachnoid hemorrhage.
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