Background and Purpose--It has been proposed that antioxidants and spin-trap agents may be neuroprotective after acute ischemia stroke. Although the antioxidant ebselen is currently in clinical trials, little is known about the effectiveness of ebselen, which has glutathione peroxidase-like and anti-inflammatory properties in embolic stroke models. Therefore, we determined the effects of ebselen when administered alone or with the thrombolytic tissue plasminogen activator (tPA), the only Food and Drug Administration-approved pharmacological agent for the treatment of stroke.

Methods--Male New Zealand White rabbits 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 rabbits received infusions of the vehicle required to solubilize ebselen. In additional rabbits, ebselen (20 mg/kg) was administered 60 minutes after embolization, either alone or in combination with tPA (0.9 or 3.3 mg/kg tPA). Behavioral analysis was conducted 24 hours after embolization, allowing determination of the effective stroke dose (P₅₀) or clot amount (mg) that produces neurological deficits in 50% of the rabbits.

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. Rabbits 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 tPA (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 tPA alone (P₅₀=3.38±0.55 mg). However, if ebselen (20 mg/kg) was administered concomitantly with low-dose tPA (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 embolic stroke, 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 tPA.