Presentation
# 5
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6th Internet World Congress for Biomedical Sciences |
Phyllis G. Paterson(1)
(1)University of Saskatchewan - Saskatoon. Canada
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The cascade of events responsible for the death of neural cells following a stroke include depletion of ATP, glutamate excitotoxicity, calcium overload, and production of strong oxidants that can overwhelm antioxidant defense. These events have been extensively reviewed (1-4). A variety of mechanisms contribute to the increase in reactive species including mitochondrial leakage, increased intracellular calcium, increased xanthine oxidase activity, altered arachidonic acid metabolism and activated neutrophils, catecholamine oxidation, and the development of lactacidosis (4-9). Restoration of blood flow to the ischemic tissue amplifies the production of free radicals (9). While the increased superoxide anion produced can adversely affect cell function, more importantly it can interact to produce powerful oxidizing agents such as the hydroxyl radical. The superoxide dismutase family can dismutate the superoxide anion into hydrogen peroxide, but the latter must be removed or it can be reduced to the hydroxyl radical by reduced transition metals such as ferrous iron. The hydroxyl radical is damaging to cells by causing DNA strand breaks, protein oxidation, and lipid peroxidation. The latter is particularly damaging since once initiated, this starts a chain of peroxidations, ultimately resulting in the formation of lipid peroxyl radicals and lipid hydroperoxides that disturb cell membrane function. The lipid hydroperoxides in the presence of iron can be converted to alkoxy and peroxy radicals resulting in new chains of lipid peroxidation (4-10). An upregulation of pro-inflammatory genes occurs as a result of the oxidative insult with upregulation of cell adhesion molecules on the endothelium and leukocyte infiltration, resulting in an inflammatory state that also makes an important contribution to cell damage (11,12).
Glutathione (GSH) has a central role within the finely tuned network of antioxidant systems that can respond to the oxidative insult. The key importance of GSH and glutathione peroxidase to efficient peroxide scavenging in neural cells has been reviewed (3,6,13). This is carried out by enzymes that dismutate hydrogen peroxide into water and molecular oxygen. Catalase can remove only hydrogen peroxide, and is effective only at high concentrations of this peroxide. Of more importance is the family of glutathione peroxidases that remove not only hydrogen peroxide but also lipid peroxides (8,10,14). Glutathione peroxidase activity is dependent upon the presence of GSH which is oxidized in the process. As the efficiency of glutathione peroxidase for scavenging peroxides increases as a function of GSH concentration, small changes in GSH can have a large influence on the ability of the cell to scavenge peroxides (7). GSH is also used by glutathione-S-transferases to detoxify the aldehyde breakdown products of lipid hydroperoxides (15). GSH functions to regenerate vitamin E that is important for scavenging lipid peroxyl radicals in membranes; GSH reduces oxidized ascorbate, which directly reduces the alpha-tocopherol radical (5,7,8,10,14). GSH exerts direct antioxidant effects and influences other cell processes important in determining the extent of cell injury -reviewed in (1)(16)-. These include prevention of the formation of advanced glycation products and inhibition of the transcription factor, NFkB that is required for the expression of pro-inflammatory genes.
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