Dexamethasone has been consistently shown to prevent HIE in a neonatal rat model. We investigated the role of oxygen free radicals, lipid peroxidation and apoptosis in this phenomenon.

Model: 7-day old rat pups underwent unilateral carotid artery ligation and exposure to 8% oxygen for 2.5 hours. Animals were pretreated with dexamethasone (0.1 mg/kg) or vehicle.

Measurements: Spectrophotometric assay for superoxide radical, gas chromatography/mass spectrometry for hydroxyl radical and lipid peroxidation, anti-nitrotyrosine immunohistochemistry for peroxynitrite, Northern analysis for c-fos, end-labelling of 3′-OH DNA with terminal deoxytransferase and detection with fluorescent antibody, DNA laddering.

Results: Dexamethasone- and vehicle-treated animals showed significant elevations in superoxide (p <0.05), anti-nitrotyrosine staining, lipid peroxidation (p = 0.007) but not hydroxyl radical (p = 0.45) 1 hour after reoxygenation. There was no significant difference between dexamethasone- and vehicle-treated groups with respect to the above. C-fos induction was inhibited by dexamethasone. Markers of apoptosis (DNA end- labelling and DNA laddering) were suppressed by dexamethasone.

Conclusion: Apoptosis contributes to HIE-mediated cell death in this model. The observation that it is possible to inhibit cell death following HIE, with dexamethasone pretreatment, despite unaffected free radical and hydroperoxide generation, suggests the exciting possibility that post-insult interventions to inhibit apoptosis may also be able to limit tissue injury.

Support: Heart and Stroke Foundation of Canada, Medical Research Council of Canada and the Ackman Travelling Scholarship, University of Melbourne, Australia.