title: 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.
abstract: Oxygen free radical generation may have important secondary damaging effects after the onset of cerebral ischemia. Free radical scavengers have been used successfully in attenuating neuronal damage in the reperfusion period in 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 PBN has been demonstrated to reduce infarct volume in focal ischemia, neuroprotection has not been evaluated with S-PBN. The present study was designed to evaluate the neuroprotective effect of PBN and S-PBN compared to vehicle in a focal embolic middle cerebral artery (MCA) cerebral ischemia model in rats. 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 PBN or S-PBN (both 100 mg/kg/day x 3 days, intraperitoneally) 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 stained coronal slices 72 h after the ischemic insult. Two-hour postischemia administration of PBN or S-PBN significantly improved neurobehavioral scores at 24 h following MCA embolization (both P < 0.01). The percentage of infarct volume for animals receiving vehicle was 32.8 +/- 9.4%. Two-hour delayed administration of PBN and S-PBN achieved a 35.4% reduction in infarct volume 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 may be involved in brain damage in this model and 2-h delayed postischemia treatment with PBN and S-PBN may have neuroprotective effects in focal cerebral 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 brain via damaged vessels.
authors.affiliation: Division of Neurology, University of Alberta, Edmonton, Alberta, T6G 2B7, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.forename: A
authors.initials: A
authors.lastname: Shuaib
mesh_terms: D000818:Animals; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000627:therapeutic use*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D003497:Cyclic N-Oxides; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000139:chemically induced / Q000150:complications; D007274:Injections, Intraperitoneal; D008297:Male; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009589:Nitrogen Oxides / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects; D013917:Thrombin
chemical_list: D001557:Benzenesulfonates; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; C094272:N-tert-butyl-(2-sulfophenyl)nitrone; C029217:phenyl-N-tert-butylnitrone; D013917:Thrombin