Abstract

Introduction

Materials & Methods

Results

Discussion & Conclusion

References

Discussion
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In the first study, SAA deficiency was confirmed by the dramatic reduction in the GSH concentration of liver, an important site of GSH synthesis (18). While regional differences were apparent in brain GSH status, all brain regions studied showed the trend towards a decrease in GSH concentration with SAA deficiency. Thus, it appears that all regions are susceptible to the deficiency; we believe the lack of statistically significant results for striatum and hippocampus relate to the small sample size of the study (n=6/group). We hypothesize that this modest depletion of brain GSH by the reduced supply of dietary precursors may be important at the time of a stroke when the rate of GSH utilization and the need for synthesis are increased. Thorburne and Juurlink (41) have shown that relatively small changes in intracellular GSH alter the ability of oligodendroglial cells to handle oxidative stress. A better understanding of the significance of these findings will next be determined by investigating whethe r an acute, severe SAA deficiency or a chronic moderate protein deficiency has effects on brain GSH metabolism sufficient to magnify the tissue damage occurring in a rodent model of hypoxia-ischemia.

Protein-energy status appears to be an important factor in the elderly patient presenting with a stroke. While epidemiological studies have shown a protective effect of increased dietary protein on stroke mortality and incidence (42-44), protein-energy malnutrition remains a relatively common problem in the elderly (45-48) that is both underdiagnosed and undertreated (17, 45). Evidence has now emerged from Spain (49), Sweden (50), and the United Kingdom (51) that suboptimal protein-energy status is present in a significant proportion of patients at the time of an acute stroke. These assessments, using both biochemical and anthropometric markers of protein-energy status, were done at timepoints varying from less than 24 hours to 4 days following the stroke. Axelsson et al. (50) and Dávalos et al. (49) reported poor protein-energy status in approximately 16% of acute stroke admissions. A study from Korea (52) documented undernutrition to be as high as 25% in patients with cerebral infarction and 62% in p atients with intracerebral hemorrhage as compared to 13% in age-matched controls. Since their anthropometric assessments were done up to 1 week following admission, nutritional problems secondary to the stroke may partially account for the higher proportion of malnourished patients. There are two other important findings from these studies. Both Davalos et al. (49) and Gariballa et al. (51) have shown a correlation between the clinical markers of protein-energy malnutrition at admission for acute stroke and increased risk of morbidity and mortality. Secondly, there is good evidence that nutritional status deteriorates during the stroke patient’s hospital stay (50, 51). Canadian data suggest that rates of malnutrition can be as high as 49% among stroke patients at the time of transfer from acute treatment to rehabilitation services (53). While nutritional problems occurring secondary to the stroke will be major contributors to this high rate, these data also suggest that nutritional intervention is not likely sufficient in the immediate postinjury period to optimize antioxidant defense mechanisms.

Our preliminary studies suggest that total GPX activity in at least some brain regions is not sensitive to either deficient levels of dietary Se or to excess Se provided above the dietary requirement. Other brain regions are currently being examined for GPX activity and GPX1 protein and mRNA to fully answer this question. It may be that the tissue hierarchy for Se partitioning protects the brain when Se is in short supply. Previous work of Lei et al. (31) has illustrated important differences among tissues in how dietary Se regulates the expression of selenoproteins. In contrast to liver, heart, kidney, and lung, dietary Se deficiency causes a much smaller decrease in testis GPX1 activity and has no influence on GPX1 mRNA; activity and mRNA level for GPX4 are unaltered. In similar studies in liver, heart, and thyroid, Bermano et al. (54) have also confirmed the differences in regulation of expression of these two enzymes by dietary Se both within and among tissues. It has also been shown that even in tissues that are sensitive to suboptimal dietary Se that supplementing Se above nutritional requirement does not further increase GPX1 and GPX4 activity (31, 54, 55). The important question, however, still remains unanswered, and this is whether the Se status of the individual alters the ability to upregulate these selenoproteins in brain under conditions of increased oxidative stress generated during acute stroke and the reperfusion period.

In summary, in contrast to cardiovascular disease, the impact of nutritional status on the prevention and outcome of stroke has received little attention. Nutritional intervention has previously been appreciated in prevention strategies for treating risk factors for stroke such as hypertension and diabetes mellitus. We have presented a mechanism by which nutritional status in the acute stroke and immediate postinjury periods may affect outcome by regulating key components of antioxidant defense. To date, we have evidence that a short-term dietary sulfur amino acid deficiency will compromise the GSH status of a number of brain regions. We are also studying whether cellular glutathione peroxidase in the same brain regions is influenced by dietary selenium; our preliminary studies to date suggest that glutathione peroxidase activity in brain is protected when dietary selenium is in short supply. As nutritional status is compromised for a significant proportion of patients during acute stroke, the current challenge is to determine whether nutritional intervention might play a role in neuroprotective strategies aimed at improving stroke outcome.

Acknowledgements

This work has been supported by the University of Saskatchewan President’s NSERC Research Fund and the Heart and Stroke Foundation of Saskatchewan. The author is grateful to Dr. B. Juurlink for many helpful discussions and to L. Andersen, E. Eftekharpour, J. Fabe, and M. Maboudian-Esfahani for assistance with tissue collection and assays.

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