The aim of this research project is to elucidate the mechanism of carbon mon-oxide-mediated brain lipid peroxidation, which we have identified in a rat model of CO poisoning. CO is the leading cause of death by poisoning in the United States, and 12% or more of survivors suffer delay neurologic deterioration after the acute insult. The mechanism for this delayed process is unknown, but it is hypothesized to be an oxidative injury. Our hypothesis is that lipid peroxidation in our model represents what is popularly described as an """"""""ischemia-reperfusion"""""""" phenomenon. We propose to study the time course for lipid peroxidation in greater detail over the days following CO exposure, and to correlate lipid peroxidation with functional changes using (14C) 2-deoxyglucose imaging and phosphorous NMR spectroscopy. The mechanism for brain lipid peroxidation will be studied using various techniques. We will evaluate the role of xanthine oxidase by assessing the impact of enzyme inhibition, using tungsten, on the development of lipid peroxidation after CO poisoning. The time course of xanthin dehydrogenase to xanthine oxidase conversion after CO poisoning will also be measured. We will evaluate the involvement of oxidants by measuring brain H202 at various times subsequent to CO exposure; and also by determining the impact of infusion of dimethylthiourea, an H202 scavenger, desferrioxamine, an iron chelator, and liposome-encapsulated antioxidant enzymes (superoxide dismutase and/or catalase) on CO-mediated lipid peroxidation. We also propose to study in greater detail our observation involving hyperbaric oxygen (HBO) antagonism of CO-mediated lipid peroxidation. These studies will involve further in vivo experiments, administration of HBO at different times after CO poisoning; and further in vitro experiments using xanthine oxidase generated radicals to assess the impact of 02 concentration and PH on linoleic acid peroxidation.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Toxicology Subcommittee 2 (TOX)
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University of Pennsylvania
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