Efficacy of disodium 4-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059), a free radical trapping agent, in a rat model of hemorrhagic stroke.
Because free radical mechanisms may contribute to brain injury in hemorrhagic stroke, the effect of the free radical trapping agent disodium 4-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059) was investigated on outcome following intracerebral hemorrhage (ICH) in rat. ICH was induced in 20 adult rats by infusion of collagenase into the caudate-putamen. Thirty minutes later rats were treated with NXY-059 (50 mg/kg subcutaneous plus 8.8 mg/kg/h for 3 days subcutaneous delivered via implanted osmotic pumps) or saline (equivalent volumes). Magnetic resonance imaging 24 h after ICH confirmed that the hemorrhage was uniform in the two groups, and subsequent imaging at 7 and 42 days post-ICH showed that the hematoma resolved similarly in the two groups. Behavioral testing on days 1, 3, 7, 14, and 21 after ICH showed that rats treated with NXY-059 had significantly decreased neurological impairment at all times. Deficits in skilled forelimb use 4-5 weeks post-ICH, and in striatal function 6 weeks post-ICH, were not reduced by treatment with NXY-059. Treatment with NXY-059 significantly reduced the neutrophil infiltrate observed 48 h post-hemorrhage in the vicinity of the hematoma, and the number of TUNEL-positive cells 48 h post-hemorrhage at the hematoma margin. However, by 6 weeks there were no differences in neuronal densities in treated and control rats.
Peeling
J
J
Department of Pharmacology and Therapeutics, The University of Manitoba, 770 Bannatyne Avenue, R3E 0W3, Winnipeg, MN, Canada. jpeeling@ms.umanitoba.ca
Del Bigio
M R
MR
Corbett
D
D
Green
A R
AR
Jackson
D M
DM
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001557:Benzenesulfonates; D001772:Blood Cell Count; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000008:administration & dosage*; D006406:Hematoma / Q000276:immunology / Q000473:pathology; D007260:Infusion Pumps; D007279:Injections, Subcutaneous; D008279:Magnetic Resonance Imaging; D008297:Male; D009048:Motor Skills / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D009589:Nitrogen Oxides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010865:Pilot Projects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D016896:Treatment Outcome
D001557:Benzenesulfonates; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; C120851:disufenton sodium