Ebselen protects both gray model of focal and white matter in a rodent cerebral ischemia

Background and Purpose-The neuroprotective efficacy of an intravenous formu lation of the antioxidant ebselen has been comprehensively assessed with sp ecific regard to conventional quantitative histopathology, subcortical axon al damage, neurological deficit, and principal mechanism of action. Methods-Transient focal ischemia (2 hours of intraluminal thread-induced is chemia 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 assesse d 24 hours after ischemia. Gray matter damage was evaluated by quantitative histopathology. Axonal damage was determined with amyloid precursor protei n immunohistochemistry used as a marker of disrupted axonal flow and Tau-1 immunohistochemistry to identify oligodendrocyte pathology. Oxidative damag e was determined by 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxynonen al (4-HNE) immunohistochemistry. Results-Ebselen significantly reduced the volume of gray matter damage in t he cerebral hemisphere (by 53.6% compared with vehicle, P < 0.02). Axonal d amage was reduced by 46.8% (P < 0.002) and the volume of oligodendrocyte pa thology was reduced by 60.9% (P < 0.005). The neurological deficit score wa s 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), respect ively, in ebselen-treated animals. Conclusions-Delayed (2-hour) treatment with intravenous ebselen significant ly reduced gray and white matter damage and neurological deficit associated with transient ischemia. The reduction in tissue displaying evidence of ox idative stress suggests that the major mechanism of action is attenuation o f free radical damage.