Published online before print July 10, 2003, doi: 10.1161/01.STR.0000081223.74129.04
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(Stroke. 2003;34:2013.)
© 2003 American Heart Association, Inc.
Original Contributions |
Ebselen, a Seleno-Organic Antioxidant, Is Neuroprotective After Embolic Strokes in Rabbits
Synergism With Low-Dose Tissue Plasminogen Activator
From the University of California San Diego, Department of Neuroscience, La Jolla; and VASDHS and Veterans Medical Research Foundation, San Diego, Calif.
Correspondence to Dr Paul A. Lapchak, University of California San Diego, Department of Neuroscience, MTF 316, 9500 Gilman Dr, La Jolla, CA 92093–0624. E-mail plapchak{at}ucsd.edu
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.
Key Words: ischemia • neuroprotection • reperfusion • thrombolytic therapy • tissue plasminogen activator • rabbits
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