Xanthine oxidase-derived hydrogen peroxide contributes to ischemia reperfusion-induced edema in gerbil brains

The contribution of toxic O₂ metabolites to cerebral ischemia reperfusion injury has not been determined. We found that gerbils subjected to temporary unilateral carotid artery occlusion (ischemia) consistently developed neurologic deficits during ischemia with severities that correlated with increasing degrees of brain edema and brain H₂O₂ levels after reperfusion. In contrast, gerbils treated just before reperfusion (after ischemia) with dimethylthiourea (DMTU), but not urea, had decreased brain edema and brain H₂O₂ levels. In addition, gerbils fed a tungsten-rich diet for 4, 5, or 6 wk developed progressive decreases in brain xanthine oxidase (XO) and brain XO + xanthine dehydrogenase (XD) activities, brain edema, and brain H₂O₂ levels after temporary unilateral carotid artery occlusion and reperfusion. In contrast to tungsten-treated gerbils, allopurinol-treated gerbils did not have statistically significant decreases in brain XO or XO + XD levels, and reduced brain edema and brain H₂O₂ levels occurred only in gerbils developing mild but not severe neurologic deficits during ischemia. Finally, gerbils treated with DMTU or tungsten all survived, while > 60% of gerbils treated with urea, allopurinol, or saline die by 48 h after temporary unilateral carotid artery occlusion and reperfusion. Our findings indicate that H₂O₂ from XO contributes to reperfusion-induced edema in brains subjected to temporary ischemia.