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The neuroprotective efficacy of an intravenous formulation of the antioxidant ebselen has been comprehensively assessed with specific regard to conventional quantitative histopathology, subcortical axonal damage, neurological deficit, and principal mechanism of action.Transient focal ischemia (2 hours of intraluminal thread-induced ischemia with 22 hours of reperfusion) was induced in the rat. Ebselen (1 mg/kg bolus plus 1 mg/kg per hour IV) or vehicle was administered at the start of reperfusion and continued to 24 hours. Neurological deficit was assessed 24 hours after ischemia. Gray matter damage was evaluated by quantitative histopathology. Axonal damage was determined with amyloid precursor protein immunohistochemistry used as a marker of disrupted axonal flow and Tau-1 immunohistochemistry to identify oligodendrocyte pathology. Oxidative damage was determined by 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 4-hydroxynonenal (4-HNE) immunohistochemistry.Ebselen significantly reduced the volume of gray matter damage in the cerebral hemisphere (by 53.6% compared with vehicle, P <0.02). Axonal damage was reduced by 46.8% (P <0.002) and the volume of oligodendrocyte pathology was reduced by 60.9% (P <0.005). The neurological deficit score was reduced by 40.7% (P <0.05) and the volume of tissue immunopositive for 8-OHdG and 4-HNE was reduced by 65% (P <0.002) and 66% (P <0.001), respectively, in ebselen-treated animals.Delayed (2-hour) treatment with intravenous ebselen significantly reduced gray and white matter damage and neurological deficit associated with transient ischemia. The reduction in tissue displaying evidence of oxidative stress suggests that the major mechanism of action is attenuation of free radical damage.