Neuroprotection by 2-h postischemia administration of two free radical scavengers, alpha-phenyl-n-tert-butyl-nitrone (PBN) and N-tert-butyl-(2-sulfophenyl)-nitrone (S-PBN), in rats subjected to focal embolic cerebral ischemia

Oxygen free radical generation may have important secondary damaging effect s after the onset of cerebral ischemia. Free radical scavengers have been u sed successfully in attenuating neuronal damage in the reperfusion period i n transient forebrain ischemia. There are limited data on effectiveness in models of focal ischemia. Two free radical scavengers, alpha-phenyl-n-tert- butyl-nitrone (PBN) and N-tert-butyl-(2-sulfophenyl)-nitrone (S-PBN), have been shown to reduce oxidative-stress-induced neuronal injury. Whereas PEN has been demonstrated to reduce infarct volume in focal ischemia, neuroprot ection has not been evaluated with S-PBN. The present study was designed to evaluate the neuroprotective effect of PEN and S-PBN compared to vehicle i n a focal embolic middle cerebral artery (MCA) cerebral ischemia model in r ats. Wistar rats were randomly divided into three groups (n = 10 each group ). Animals in the control group received vehicle and those in the treatment groups were treated with PEN or S-PBN (both 100 mg/kg/day x 3 days, intrap eritoneally) starting 2 h after the introduction of an autologous thrombus into the right-side MCA. The neurological outcome was observed and compared before and after treatment and between groups. The percentage of cerebral infarct volume was estimated from 2,3,5-triphenyltetrazolium chloride stain ed coronal slices 72 h after the ischemic insult. Two-hour postischemia adm inistration of PEN or S-PBN significantly improved neurobehavioral scores a t 24 h following MCA embolization (both P < 0.01). The percentage of infarc t volume for animals receiving vehicle was 32.8 +/- 9.44b. Two-hour delayed administration of PEN and S-PBN achieved a 35.4% reduction in infarct volu me in treatment groups when compared with animals receiving vehicle (PBN vs control, 21.2 +/- 10.9% vs 32.8 +/- 9.4%; P < 0.05; S-PBN vs control, 21.2 +/- 13.1%, (P < 0.05). These data indicate that free radical generation ma y be involved in brain damage in this model and 2-h delayed postischemia tr eatment with PEN and S-PBN may have neuroprotective effects in focal cerebr al ischemia. As S-PBN does not normally cross the blood-brain barrier, the neuroprotection evident in this study may be explained by entry into the br ain via damaged vessels. (C) 2000 Academic Press.