Ebselen, a Seleno-Organic Antioxidant, Is Neuroprotective After Embolic Strokes in Rabbits

Abstract

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 (P 50 ) or clot amount (mg) that produces neurological deficits in 50% of the rabbits. Results-A drug is considered neuroprotective if it significantly increases the P 50 compared with the vehicle-treated control group. The P 50 of controls 24 hours after embolization was 1.35Ϯ0.30 mg. Rabbits treated 5 minutes after embolization with 10, 20, or 50 mg/kg ebselen had P 50 values of 2.12Ϯ0.56, 2.82Ϯ0.75 (PϽ0.05), and 0.49Ϯ0.54 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 (P 50 ϭ1.69Ϯ0.32 mg). When tPA (3.3 mg/kg) was infused 60 minutes after embolization and ebselen (20 mg/kg) was injected at either 5 (P 50 ϭ2.98Ϯ0.18 mg) or 60 (P 50 ϭ3.60Ϯ0.79 mg) minutes, there was no additional neuroprotective effect compared with tPA alone (P 50 ϭ3.38Ϯ0.55 mg). However, if ebselen (20 mg/kg) was administered concomitantly with low-dose tPA (0.9 mg/kg) 60 minutes after embolization, the P 50 was 3.52Ϯ0.73 mg (PϽ0.05), indicating a synergistic effect of the drug combination because neither alone was effective (P 50 ϭ1.69Ϯ0.32 and 1.54Ϯ0.36 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.

A novel approach to screening for new neuroprotective compounds for the treatment of stroke

“…The improvement in behavioral outcome relative to the control rabbits that we observed was better than that seen with the antioxidant ebselen (Lapchak and Zivin, 2003) and similar to that seen with several other compounds including the phenylpropanoid chlorogenic acid (Lapchak, 2007) and the spin trap NXY-059 (Lapchak et al, 2004b). This result further supports the use of the in vitro chemical ischemia assay in combination with the biochemical assays as an initial screen for potential neuroprotective compounds for the treatment of stroke.…”

Effects of ebselen versus nimodipine on cerebral vasospasm subsequent to experimental subarachnoid hemorrhage in rats

“…[3][4][5][6][7]10,11 Studies in experimental models have demonstrated that ebselen has either a significant or at least a possible neuroprotective effect. 3,27 The neuroprotective effects of ebselen are thought to be mainly mediated by its reduction of hydrogen peroxide and lipid hydroperoxides via its interaction with the thioredoxin system, 10 and its ability to mimic glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase. 3 Porciuncula et al determined that ebselen prevents the lipid peroxidation induced by glutamine and protects cerebellar granular neurons against glutamate neurotoxicity.…”

Selenium: its role as antioxidant in human health

“…In animal studies, ebselen can have cardioprotective effects when administered orally before ischemic reperfusion, and this may involve the induction of stress protein HSP27 and the preservation of glutathione (GSH) [34]. Ebselen has also been shown to have a neuroprotective effect on stroke in a rabbit embolic stroke model, and when it was administered concomitantly with a thrombolytic tissue plasminogen activator, there were significant behavioural improvements in rabbits [35]. The efficacy of ebselen as a neuroprotective agent has also been demonstrated in humans, where there was a significant improvement in patients who were given ebselen within 24 h of stroke onset [36].…”