SOURCES AND EFFECTS OF REACTIVE OXYGEN INTERMEDIATES IN THE BRAIN

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Experiments have been performed on microglia and astrocytes cultured from cerebral cortices of mice and hamsters. We have previously demonstrated that activated rat microglia cells produce the reactive oxygen species (ROS), superoxide radical anion, within a few hours after stimulation and nitric oxide, after a period of about 10 hours to several days. Previously, we have also shown that hamster microglia releases little or no nitric oxide. We have now shown that activated mice microglia also produce nitric oxide. We have continued these studies using normal human microglia, obtained from biopsy samples, and have shown that these human microglia produce little or no nitric oxide. We have tested more than 24 chemical activators including beta-amyloid (1- 40) to determine if any one of them could activate hamster microglia to produce nitric oxide, Neither hamster nor human microglia produce NO. Human microglia have only been tested with 6 different chemical activators to determine if any of these would be successful techniques for producing nitric oxide. Thus, we have now shown that hamster microglia are similar to human microglia, and that for animal disease models in which microglia participate, it might be better to use hamsters instead of rats and mice. Since arginase catalyses the breakdown of arginine into urea and ornithine, we tested whether the inhibition of this pathway by (+)-S-2-amino-5-iodoacetamidopentanoic acid (AIAP), an inhibitor of the enzyme, arginase, could possibly produce nitric oxide production in the hamster microglia. Preliminary experiments. indicated that this inhibition did produce nitric oxide from stimulated hamster microglia.The B103 cells, derived from neuroblastoma line, are exceptional in their lack of beta-amyloid precursor protein. The cells have been grown in the presence of hydrogen peroxide as a oxidative stress. We are currently accessing the damage produced by this oxidative stress. We plan to give the same oxidative stress to these cells in the presence of added beta-amyloid precursor protein and determine if this is an antioxidant.