title: NXY-059, a novel free radical trapping compound, reduces cortical infarction after permanent focal cerebral ischemia in the rat.
abstract: Free radicals have gained wide acceptance as mediators of cerebral ischemic injury. It has previously been reported that a spin trap nitrone, alpha-phenyl-N-tert-butyl nitrone (PBN), can reduce infarct volumes in rats subjected to either permanent or transient focal cerebral ischemia. A recent study has demonstrated that NXY-059, a novel free radical trapping nitrone compound, has a neuroprotective effect against transient focal cerebral ischemia. This study was designed to determine the effect of NXY-059 in a rodent model of permanent focal cerebral ischemia. Male spontaneously hypertensive rats were subjected to permanent middle cerebral artery occlusion (MCAO) by placement of a microaneurysm clip on the middle cerebral artery (MCA). Animals were divided into three groups: (1) physiological saline given as a 1 ml/kg i.v. bolus administered 5 min post MCAO followed immediately by a continuous i.v. infusion of 0.5 ml/h of physiological saline for 24 h (n=10); (2) 30 mg/kg, 1 ml/kg, i.v. bolus of NXY-059 dissolved in physiological saline administered 5 min post MCAO followed immediately by a continuous i.v. infusion of 30 mg/kg/h, 0.5 ml/h, of NXY-059 for 24 h (n=9); (3) 60 mg/kg, 1 ml/kg, i.v. bolus of NXY-059 dissolved in physiological saline administered 5 min post MCAO followed immediately by a continuous i.v. infusion of 60 mg/kg/h, 0.5 ml/h, of NXY-059 for 24 h (n=12). Infarction was quantified after a survival period of 24 h. Differences in infarct volume were examined with one-way ANOVA following Dunnet's multiple comparison test. The percentage of cortical infarction in the saline control group was 22.6 +/- 6.8% (mean+/-S.D.) of contra-lateral hemisphere, and in the 30 mg/kg/h NXY-059-treated group was 17.4% +/- 6.8% (NS). Plasma concentration (microM/l) of NXY-059 in the 30 mg/kg/h group was 80.2 +/- 52.2 (n=9), while in the 60 mg/kg/h group plasma concentration (microM/l) of NXY-059 was 391.0 +/- 207.0 (n=10). Infarction in the 60 mg/kg/h NXY-059-treated group was significantly reduced (P=0.009) to 14.5 +/- 5%. Our preliminary data demonstrate that administration of NXY-059 (60 mg/kg/h for 24 h) ameliorates cortical infarction in rats subjected to permanent focal cerebral ischemia with 24 h survival.
authors.affiliation: Alberta Stroke Program, Department of Clinical Neurosciences, University of Calgary, Foothills Hospital, Room 1162, 1043-29th Street NW, Alberta, T2N 2T9, Calgary, Canada.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.forename: M
authors.initials: M
authors.lastname: Cheng
authors.forename: K R
authors.initials: KR
authors.lastname: Maples
authors.forename: J Y
authors.initials: JY
authors.lastname: Ma
authors.forename: A M
authors.initials: AM
authors.lastname: Buchan
mesh_terms: D000818:Animals; D001557:Benzenesulfonates; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D016166:Free Radical Scavengers / Q000097:blood / Q000493:pharmacokinetics*; D005609:Free Radicals / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000097:blood / Q000493:pharmacokinetics*; D009589:Nitrogen Oxides / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: D001557:Benzenesulfonates; D016166:Free Radical Scavengers; D005609:Free Radicals; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; C120851:disufenton sodium