Hypoxia-ischemia is accompanied by abundant corticosterone secretion that could exacerbate brain damage after the insult. The authors demonstrate that the steroid synthesis inhibitor metyrapone (150 mg/kg subcutaneously) suppresses the hypoxia-ischemia-induced rise of plasma corticosterone levels (17.3 +/- 3.6 micrograms/dL) when compared with corticosterone-treated animals (72.2 +/- 4.8 micrograms/dL) immediately after hypoxia-ischemia. In parallel, metyrapone reduced brain damage (P < 0.05). Moreover, none of the metyrapone-treated animals displayed seizures, whereas seven of eight corticosterone-treated animals had seizures after hypoxia-ischemia. Although corticosterone administration in metyrapone-treated animals elevated plasma corticosterone levels (39.0 +/- 5.3 micrograms/dL), this did not result in a subsequent increase in brain damage and seizures when compared with metyrapone-treated animals. The authors conclude that metyrapone reduces brain damage and the incidence of seizures after hypoxia-ischemia but that this effect might partially be independent from its effect on modulating plasma corticosterone levels.