Ebselen, a seleno-organic antioxidant, is neuroprotective after embolic strokes in rabbits: synergism with low-dose tissue plasminogen activator.
OBJECTIVE
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.
Lapchak
Paul A
PA
University of California San Diego, Department of Neuroscience, MTF 316, 9500 Gilman Dr, La Jolla, Calif 92093-0624, USA. plapchak@ucsd.edu
Zivin
Justin A
JA
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001393:Azoles / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000627:therapeutic use; D020766:Intracranial Embolism / Q000150:complications / Q000188:drug therapy*; D054833:Isoindoles; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016566:Organoselenium Compounds / Q000627:therapeutic use*; D011817:Rabbits; D015424:Reperfusion / Q000379:methods; D020521:Stroke / Q000150:complications / Q000188:drug therapy*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome
D000975:Antioxidants; D001393:Azoles; D005343:Fibrinolytic Agents; D054833:Isoindoles; D018696:Neuroprotective Agents; D016566:Organoselenium Compounds; C042986:ebselen; D010959:Tissue Plasminogen Activator