Abstract | BACKGROUND AND PURPOSE: 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.
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Authors | Paul A Lapchak, Justin A Zivin |
Journal | Stroke
(Stroke)
Vol. 34
Issue 8
Pg. 2013-8
(Aug 2003)
ISSN: 1524-4628 [Electronic] United States |
PMID | 12855833
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antioxidants
- Azoles
- Fibrinolytic Agents
- Isoindoles
- Neuroprotective Agents
- Organoselenium Compounds
- ebselen
- Tissue Plasminogen Activator
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Topics |
- Animals
- Antioxidants
(therapeutic use)
- Azoles
(therapeutic use)
- Behavior, Animal
(drug effects)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Drug Administration Schedule
- Drug Synergism
- Drug Therapy, Combination
- Fibrinolytic Agents
(adverse effects, therapeutic use)
- Intracranial Embolism
(complications, drug therapy)
- Isoindoles
- Male
- Neuroprotective Agents
(therapeutic use)
- Organoselenium Compounds
(therapeutic use)
- Rabbits
- Reperfusion
(methods)
- Stroke
(complications, drug therapy)
- Time Factors
- Tissue Plasminogen Activator
(adverse effects, therapeutic use)
- Treatment Outcome
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