Role of carbon monoxide (CO) in hyperthermic brain injury induced brain pathology was examined in a rat model using immunohistochemistry of the hemeoxygenase-2 (HO-2) enzyme. Exposure of rats to 4 h heat stress at 38 degrees C resulted in profound hyperthermia, breakdown of the blood-brain barrier (BBB), brain edema formation, cell damage and expression of HO-2 in several brain regions. Pretreatment with potent antioxidant compounds EGB-761 and BN-52021 markedly reduced the HO-2 expression, BBB breakdown, brain edema formation and cell damage without attenuating the hyperthermic response. This effect was most marked in animals treated with EGB-761. These observations suggest that upregulation of HO-2 representing generation of CO plays important roles in hyperthermic brain injury, and oxidative stress seems to be one of the most important signals in inducing HO-2 expression in hyperthermia, not reported earlier.