Presentation
# 5
Presentation |
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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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Contact address: |
Phyllis G. Paterson University of Saskatchewan College of Pharmacy and Nutrition 110 Science Place Saskatoon SK S7N 5C9 Canada patersnp@duke.usask.ca |
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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. Glutathione (GSH) has a central role within the finely tuned network of antioxidant systems that can respond to the oxidative insult through its functions in peroxide scavenging via glutathione-S-transferase and the family of glutathione peroxidases, regeneration of alpha-tocopherol, and inhibition of NFkB which is required for the expression of pro-inflammatory genes. Brain GSH under conditions of cerebral oxidative insult is determined by the balance among its utilization, de novo synthesis, and reduction of oxidized-glutathione by glutathione reductase. A number of investigators have shown that brain GSH levels are decreased by cerebral ischemia and reperfusion in some rat models, and that deliberate depletion of GSH by buthionine sulfoximine enhances ischemic injury in rat cerebrum. The rate of GSH synthesis is mainly controlled by cellular levels of cysteine, the limiting substrate, and the activity of gamma-glutamylcysteine synthetase, the rate-limiting enzyme for synthesis. Our laboratory has used a nutritional approach to study the effects of GSH depletion in a rat model of stroke. We have found that a deficiency of sulfur amino acids used as a model of reduced cysteine supply for synthesis depresses GSH concentration in a number of brain regions. A second study demonstrated that acute sulfur amino acid deficiency exacerbates brain damage in a rat model of global hemispheric hypoxic ischemia. Approaches described in the literature for maintaining GSH under ischemia conditions have also been targeted towards increasing its synthesis. Administering a GSH ester immediately after an ischemic insult offered neuroprotection in one study as did the delivery of N-acetylcysteine, a compound that supports GSH synthesis by acting as a cysteine precursor. Alpha-lipoic acid can also increase tissue GSH concentrations, possibly by increasing intracellular availability of cysteine. This compound is protective in some but not all studies of stroke in animal models. Discrepancies may be related to differences in route of administration, enantiomeric form, or conversion to its dithiol, dihydrolipoate. The series of studies reviewed suggests that GSH is an important determinant of the extent of secondary tissue damage in animal models of stroke. Strategies to enhance GSH in brain should be tested for their therapeutic efficacy in the human condition of stroke. (Funded by the Heart and Stroke Foundation of Saskatchewan)
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