Milde, Leslie Newberg

We examined the 21-aminosteroid U74006F, a potent inhibitor of lipid peroxidation, for potential neuroprotective effects in a canine model of complete cerebral ischemia. Two 1.5-mg/kg boluses were administered to six dogs, the first bolus 15 minutes prior to a 12-minute episode of complete cerebral ischemia and the second bolus after 11 minutes of ischemia, 1 minute prior to reperfusion. Using this dosage regimen, plasma U74006F levels of greater than 0.3 microgram/ml were maintained for up to an hour postischemia. An additional six animals received equal volumes of the citrate vehicle solution. At 24 and 48 hours postischemia, the dogs were neurologically evaluated by an observer blinded as to treatment selection. All six U74006F-treated animals had a normal neurologic outcome at 48 hours postischemia, while the citrate vehicle-treated animals all suffered moderate to severe neurologic deficits. The difference in outcome was significant at both 24 and 48 hours (p less than 0.005). Although U74006F is a 21-aminosteroid, it is not reported to possess glucocorticoid activity. This is supported by the present finding that no changes in plasma glucose concentration were observed following administration of the drug. The systemic vitamin E levels of citrate vehicle-treated animals decreased significantly (from 4.10 +/- 0.46 micrograms/ml to 2.95 +/- 0.38 micrograms/ml, p less than 0.05), whereas the vitamin E levels in U74006F-treated animals did not decrease significantly. These results suggest that U74006F may be of benefit in improving neurologic outcome when administered prior to an episode of complete cerebral ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Ten minutes of complete cerebral ischemia was produced in 18 dogs by temporary ligation of the aorta and venae cavae. Dogs were randomly assigned to one of three groups. A bolus dose of 10 μg kg −1 nimodipine, a dihydropyridine calcium entry blocker, followed by a constant infusion of 1 μg kg −1 min −1 was given at 15, 30, or 60 min post ischemia. Cerebral blood flow and metabolism were measured for 2 h postischemia. Delayed treatment with nimodipine ameliorated or reversed the cerebral hypoperfusion that routinely occurs after complete ischemia. In the groups treated at 15 and 30 min, CBF remained above 60 ml min −1 100 g −1 . In the group treated at 60 min, there was a progressive decline in CBF to 37 ml min −1 100 g −1 . Following treatment with nimodipine, CBF immediately increased and was maintained above 50 ml min −1 100 g −1 for the remainder of the study. Once treatment with nimodipine was begun, CBF was approximately double that of an untreated group. Changes in CBF reflected changes in cerebrovascular resistance. Nimodipine had no effect on cerebral metabolism. Since the postischemic hypoperfusion state is believed to contribute to the ultimate neurologic damage following complete ischemia, treatment with nimodipine, even if delayed up to 60 min, may improve the outcome.