BACKGROUND AND PURPOSE: It has been proposed that antioxidants and spin-trap agents may be neuroprotective after acute @entity63 @entity64 . Although the antioxidant ebselen is currently in clinical trials, little is known about the effectiveness of ebselen, which has @entity2041 peroxidase-like and anti-inflammatory properties in @entity64 models. Therefore, we determined the effects of ebselen when administered alone or with the thrombolytic tissue plasminogen activator ( @entity865 ), the only Food and Drug Administration-approved pharmacological agent for the treatment of @entity64 . METHODS: Male New Zealand White @entity95 were embolized by injection of a suspension of small blood clots into the middle cerebral artery via a catheter. Five minutes after embolization, ebselen (10 to 50 mg/kg) was infused intravenously. Control @entity95 received infusions of the vehicle required to solubilize ebselen. In additional @entity95 , ebselen (20 mg/kg) was administered 60 minutes after embolization, either alone or in combination with @entity865 (0.9 or 3.3 mg/kg @entity865 ). Behavioral analysis was conducted 24 hours after embolization, allowing determination of the effective @entity64 dose (P50) or clot amount (mg) that produces @entity51 in 50% of the @entity95 . RESULTS: A drug is considered neuroprotective if it significantly increases the P50 compared with the vehicle-treated control group. The P50 of controls 24 hours after embolization was 1.35+/-0.30 mg. @entity95 treated 5 minutes after embolization with 10, 20, or 50 mg/kg ebselen had P50 values of 2.12+/-0.56, 2.82+/-0.75 (P<0.05), and 0.49+/-0.54 mg, respectively. A significant neuroprotective effect was observed with the 20-mg/kg dose, but not if there was a 60-minute delay before administration (P50=1.69+/-0.32 mg). When @entity865 (3.3 mg/kg) was infused 60 minutes after embolization and ebselen (20 mg/kg) was injected at either 5 (P50=2.98+/-0.18 mg) or 60 (P50=3.60+/-0.79 mg) minutes, there was no additional neuroprotective effect compared with @entity865 alone (P50=3.38+/-0.55 mg). However, if ebselen (20 mg/kg) was administered concomitantly with low-dose @entity865 (0.9 mg/kg) 60 minutes after embolization, the P50 was 3.52+/-0.73 mg (P<0.05), indicating a synergistic effect of the drug combination because neither alone was effective (P50=1.69+/-0.32 and 1.54+/-0.36 mg, respectively). CONCLUSIONS: This study indicates that ebselen may be neuroprotective when administered shortly after an @entity64 , but the time- and dose-response analyses suggest that it has a narrow therapeutic window. Nevertheless, ebselen may be beneficial if administered concomitantly with a thrombolytic because it significantly enhanced the neuroprotective activity of low-dose @entity865 .

Ebselen, a seleno-organic antioxidant, is neuroprotective after @entity64 in XXXX : synergism with low-dose tissue plasminogen activator.

@entity64 :: ('MESH:D020521', 'Disease') :: ['embolic stroke', 'stroke'] @entity63 :: ('MESH:D007511', 'Disease') :: ['ischemia'] @entity2041 :: ('MESH:D005978', 'Chemical') :: ['glutathione'] @entity95 :: ('9986', 'Species') :: ['Rabbits', 'rabbits'] @entity51 :: ('MESH:D009461', 'Disease') :: ['neurological deficits'] @entity865 :: ('CHEBI:61432', 'Chemical') :: ['tPA']
@entity95 :: (9986,Species) :: ['rabbits']
