NEUROPROTECTIVE EFFICACY OF EBSELEN, AN ANTIOXIDANT WITH ANTIINFLAMMATORY ACTIONS, IN A RODENT MODEL OF PERMANENT MIDDLE CEREBRAL-ARTERY OCCLUSION

1 The aim of this study was to investigate whether delayed treatment w ith the anti-oxidant and antiinflammatory agent ebselen reduces the vo lume of infarction in a rodent model of permanent focal cerebral ischa emia. 2 Ebselen (10 or 30 mg kg(-1)) or vehicle was administered by ga vage 30 min and 12 h after the induction of cerebral ischaemia by perm anent occlusion of the left middle cerebral artery (MCA). Animals were killed 24 h following MCA occlusion, and the volumes of ischaemic dam age in the ebselen and control groups were evaluated by quantitative h istopathology. 3 Ebselen was quickly absorbed following oral (gavage) administration and reached peak levels in the plasma by 1 h post-admin istration (plasma selenium level of 0.68+/-0.04 and 0.84+/-0.1 mu g ml (-1) for 10 and 30 mg kg(-1), respectively, compared to control level of 0.51+/-0.02 mu g kg(-1)). 4 Treatment with the lower dose of ebsele n (10 mg kg(-1)) significantly (P < 0.01) reduced the volume of infarc tion in the cerebral hemisphere and cerebral cortex (by 31.8% and 36.7 %, respectively compared with the placebo group). 5 The neuroprotectiv e efficacy of the higher dose ebselen (30 mg kg-l) was less than that of the lower dose ebselen (10 mg kg(-1)). The volume of ischaemic dama ge in the cerebral hemisphere was reduced by 23.7% (P<0.02), and cereb ral cortex by 27.5% (P<0.01). 6 Both doses of ebselen (10, 30 mg kg(-1 )) had no therapeutic efficacy on the caudate nucleus, where ischaemia was most severe, in this model. 7 Free radical-mediated injury is nor mally associated with reperfusion of ischaemic tissue. The present res ults suggest that oxidative injury is also a significant contributor t o brain damage in models of maintained (permanent) ischaemia and that ebselen is effective in attenuating this free radical-induced damage.