Journal of Neurochemistry Lippincott—Raven Publishers, Philadelphia © 1997 International Society for Neurochemistry Dexamethasone Prevents Hypoxia / Ischemia-Induced Reductions in Cerebral Glucose Utilization and High-Energy Phosphate Metabolites in Immature Brain U. I. Tuor, ~J. Y. Yager, S. Bascaramurty, and ~M. R. Del Bigio Biosystems, Institute for Biodiagnostics, National Research Council of Canada; ~Department of Pathology, University of Manitoba, Winnipeg, Manitoba, and *Department of Pediatrics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada Abstract: We examined the potential importance of dex- amethasone-mediated alterations in energy metabolism in providing protection against hypoxic—ischemic brain damage in immature rats. Seven-day-old rats (n = 165) that had been treated with dexamethasone (0.1 mg/kg, i.p.) or vehicle were assigned to control or hypoxic—isch- emic groups (unilateral carotid artery occlusion plus 2—3 h of 8% oxygen at normothermia). The systemic availabil- ity of alternate fuels such as /3-hydroxybutyrate, lactate, pyruvate, and free fatty acids was not altered by dexa- methasone treatment, and, except for glucose, brain lev- els were also unaffected. At the end of hypoxia, levels of cerebral high-energy phosphates (ATP and phosphocre- atine) were decreased in vehicle- but relatively preserved in dexamethasone-treated animals. The local cerebral metabolic rate of glucose utilization (ICMRgI) was de- creased modestly under control conditions in dexametha- sone-treated animals, whereas cerebral energy use mea- sured in a model of decapitation ischemia did not differ significantly between groups. The ICMRgI increased markedly during hypoxia—ischemia (p < 0.05) and re- mained elevated throughout ischemia in dexamethasone- but not vehicle-treated groups, indicating an enhanced glycolytic flux with dexamethasone treatment. Thus, dex- amethasone likely provides protection against hypoxic— ischemic damage in immature rats by preserving cerebral ATP secondary to a maintenance of glycolytic flux. Key Words: Glucose metabolism—ATP—Glucocorticoids— Glycolysis— ~3-Hydroxybutyrate—Neonatal rats. J. Neurochem. 69, 1954—1963 (1997). We have shown in several studies that dexametha- onstrated that hypothermia, an increase in cerebral blood flow, or alterations in antioxidant enzymes can- not explain dexamethasone’ s neuroprotective action (Barks et al., 1991; Tuor et al., 1993a,b). The relative hyperglycemia observed in dexamethasone-treated ani- mals potentially contributes to the neuroprotection. However, in several studies we have found that dexa- methasone was effective even if the animals were hy- poglycemic, e.g., fasted animals (Barks et a!., 1991; Tuor et al., 1993a,b; Tuor and Del Bigio, 1996). Neu- roprotection nevertheless appears to be mediated by glucocorticoid receptors, as a glucocorticoid antago- nist, RU38486, inhibits the protective response, and other glucocorticoids are also protective (Tuor and Del Bigio, 1996). Finally, dexamethasone treatment is no longer effective in rats by 4 weeks of age, indicating that there is an age dependence of the neuroprotective effect (Tuor et al., 1995). The present study investigates directly several po- tential mechanisms of action of dexamethasone by fo- cusing on whether dexamethasone alters either brain metabolism or the levels of energy substrates present in the blood or brain. For example, one way in which dexamethasone could reduce tissue susceptibility to ischemic damage is by reducing the cerebral require- ments for energy substrates and thereby delaying en- ergy failure during ischemia (Ginsberg et al., 1992; Ames et al., 1995; Yager and Asselin, 1996). Indeed, studies in adult animals have demonstrated that local cerebral glucose utilization is decreased in some re- sone administered to immature but not mature rats be- fore a hypoxic—ischemic insult prevents the cerebral infarction observed in this model of unilateral ischemia with hypoxia (Barks et al., 1991; Chumas et al., 1993; Tuor et al., 1995). Several studies have also examined whether some of the physiological changes that poten- tially occur with dexamethasone treatment can explain dexamethasone’ s effects, and these studies have dem- Received May 2, 1997; revised manuscript received June 13, 1997; accepted June 16, 1997. Address correspondence and reprint requests to Dr. U. I. Tuor at Biosystems, Institute for Biodiagnostics, National Research Council of Canada, 435 Ellice Avenue, Winnipeg, Manitoba R3B 1Y6, Can- ada. Abbreviations used: CEU, cerebral energy utilization; 2-DG, 2- deoxyglucose; LC, lumped constant; ICMRgI, local cerebral meta- bolic rate of glucose utilization; PCR, phosphocreatine. 1954