The goals are to assess the production, reactions, and detoxification pathways of hydrogen peroxide and oxy-radicals within the nervous system. Experiments will concentrate on catecholamine neurons, which provide an arry of drug-mediated tools that facilitate manipulations in vitro and in vivo, and anatomical tools that permit the visualization of these neurons where they exist intermingled with other cell types. For example, catecholamine levels can be lowered (e.g., alpha-methyl-p-tyrosine) or raised (e.g., L-dopa), and monoamine neurons can be visualized under the fluorescence microscope or by electron microscopy. A major tool will be the investigation of neurotoxins that appear to operate via the formation of hydrogen peroxide and oxy-radicals. Organotypic cultures of nervous system will studied; experiments with animals are also planned. We are particularly interested in the role that monoamine oxidase may play as a primary generator of hydrogen peroxide within monoamine neurons. Hydrogen peroxide, in turn, serves as precursor of the highly-reactive hydroxyl radical. The immediate research goals are the amplification of experiments that are already under way. These include: 1) the study of the neurotoxin, MPTP; 2) histochemical evaluation of intracellular levels of GSH (reduced glutathione) as an index of oxidative stress; and 3) development of technology to detect the hydroxyl radical within catecholamine neurons. The long range goals are 1) to apply the new methodology to study other neurotoxins or other procedures that appear to produce an oxidative stress in the nervous system (e.g., hyperbaric oxygenation, ischemia, reperfusion stress) and 2) to evaluate other aspects of GSH metabolism that can provide an index of oxidative stress (study of GSSG, mixed disulfides, and GSH adducts with catecholamines). These studies will help to define the role of peroxides and oxy-radicals in damage to the nervous system.
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