This proposed investigation will study the role of oxygen radicals in brain injury due to hyperbaric oxygen exposure (rats) and an experimental stroke induced by carotid artery ligation (Mongolian gerbils). We will determine the ability of intravenously or intraperitoneally injected superoxide dismutase, catalase, and/or Alpha-tocopherol-containing liposomes and polyethyleneglycol-derivatized superoxide dismutase and catalase to modulate brain injury. This will provide a novel approach for probing mechanisms of oxygen radical-mediated brain injury due to hyperbaric oxygen and focal ischemia. Liposome entrapment mediates intracellular transfer of enzymes while polyethyleneglycol derivatization increases circulating half-life of enzymes from minutes to days. Tissue distribution and uptake of injected enzymes will be measured by isotopic, fluorescence microscopy and light and electron microscope-level immunocytochemistry. The kinetics of tissue uptake and half-life of injected enzymes will be studied in both rats and gerbils. Antioxidant enzyme-dependent alteration of oxygen radical injury to brain will be measured using biochemical indices such as onset of convulsions (hyperbaric oxygen only), quantitative histopathology (stroke model only), oxygen radical generation, H2O2 generation, lipid peroxidation, glutathione oxidation and glutathione disulfide formation. Thus, indices of oxygen radical-associated brain injury will be studied using a combined biochemical and pathology approach. Recently developed drug delivery technologies will provide a set of controllable experimental conditions where the role of specific reduced oxygen species in causing brain injury during dysoxia can be defined. This may provide the basis for future pharmacologic modification of tissue injury during stroke and extend the usefulness of oxygen in hyperbaric medicine.
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