Though it has been suggested that brain is ischemic around intracerebral hemorrhages (ICHs), blood flow studies are contradictory - reporting decreases, little change, and increases of blood flow. The investigators hypothesize that these contradictory findings may be due to the opposing actions of mass effect and glutamate. Mass effect from hemorrhages would decrease blood flow and produce tissue hypoxia. Glutamate, derived from blood plasma, lysed red blood cells, and injured brain cells, would increase blood flow and metabolism. Lactate also increases around ICHs; their porcine data shows lactate increases of ten-fold in white matter and four-fold in gray matter without changes of ATP. They propose that these lactate increases are partly due to mild hypoxia around hematomas without associated ischemia. Aerobic glycolysis to lactate may occur because of excitotoxic concentrations of glutamate around ICHs. These studies propose to test the hypothesis that increased blood flow and metabolism around ICHs are due to actions of glutamate by measuring local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCGU) using autoradiographic techniques in rats at different times following ICH and determining whether GLU antagonists prevent the increases of LCBF and LCGU. To determine whether moderate hypoxia exists around ICH, tissue oxygen concentrations will be measured using oxygen electrodes, and the induction of hypoxia inducible factor (HIF) and its target genes will be assessed using Western blots, Northern blots, and in situ hybridization. DNA microarrays will be used to determine whether the pattern of gene expression in tissue around rat ICH is similar to that produced by hypoxia, excitotoxins, and/or ischemia. They also postulate that LGU, released into brain following ICH, acts on GLU receptors to mediate cell stress and cell death and to increase lactate around ICHs; therefore, peri-hematomal glutamate and lactate concentrations will be measured using microdialysis in the rat ICH model. They will test whether AMPA/KA and NMDA glutamate receptor antagonists decrease cell stress, cell death, and lactate concentrations in the rat ICH model. The final experiments will address the hypothesis that excitotoxic injury due to ICH will be different in white matter versus gray matter because AMPA/KA receptors predominate in white matter and glutamate uptake will differ in white matter compared to gray matter. Because hemorrhages can be placed selectively in white matter or in gray matter using the porcine ICH model, it will be used to measure extracellular glutamate concentrations with microdialysis around hemorrhages in white matter and in gray matter. The porcine ICH model will also be used to determine if AMPA/KA receptor antagonists are superior to NMDA antagonists for decreasing cell death, cell stress, edema, and lactate around ICH located in white matter and compared to ICH located in gray matter. These studies address mechanisms of injury due to ICH and test probable therapies that could be used in patients with ICH.
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