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Ebselen, a seleno-organic antioxidant, is neuroprotective after embolic strokes in rabbits: synergism with low-dose tissue plasminogen activator.

AbstractBACKGROUND 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.
AuthorsPaul A Lapchak, Justin A Zivin
JournalStroke (Stroke) Vol. 34 Issue 8 Pg. 2013-8 (Aug 2003) ISSN: 1524-4628 [Electronic] United States
PMID12855833 (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.)
Chemical References
  • Antioxidants
  • Azoles
  • Fibrinolytic Agents
  • Isoindoles
  • Neuroprotective Agents
  • Organoselenium Compounds
  • ebselen
  • Tissue Plasminogen Activator
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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