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.