NXY-059, a free radical--trapping agent, substantially lessens the functional disability resulting from cerebral ischemia in a primate species.
OBJECTIVE
NXY-059 is a novel nitrone with free radical-trapping properties that has a considerable neuroprotective effect in rats. We have now examined the efficacy of this drug at reducing long-term functional disability in a primate model of stroke.


METHODS
Twelve monkeys were trained and tested on a variety of behavioral tasks used to dissociate and quantify motor and spatial deficits. Five minutes after permanent occlusion of the right middle cerebral artery, monkeys received a 1-mL intravenous infusion of either saline or NXY-059 (28 mg x kg(-1)), and osmotic minipumps, model 2001D, were implanted subcutaneously to provide continuous drug or saline infusion for 48 hours. Drug-filled pumps released NXY-059 at 16 mg x kg(-1) x h(-1). The monkeys were retested 3 and 10 weeks after surgery to assess functional disability. Surgery, behavioral testing, and histology were all done blinded to treatment condition.


RESULTS
NXY-059-treated monkeys were significantly better at reaching with their hemiparetic arm than were saline-treated monkeys when retested 3 weeks (P:<0.01) and 10 weeks (P:<0.01) after surgery. Drug treatment also significantly lessened the degree of spatial perceptual neglect (P:<0.01), a debilitating though ameliorating consequence of this infarct. NXY-059 treatment reduced the overall amount of brain damage by >50% of saline-treatment values, with similar levels of protection afforded to both white and gray matter.


CONCLUSIONS
This novel drug has a substantial protective effect, lessening the disability caused by an experimentally induced stroke in a primate species. These findings provide considerable encouragement for the clinical development of NXY-059.
Marshall
J W
JW
MRC Comparative Cognition Team, Department of Experimental Psychology, University of Cambridge (UK). jwbm2@cus.cam.ac.uk
Duffin
K J
KJ
Green
A R
AR
Ridley
R M
RM
D000704:Analysis of Variance; D000818:Animals; D001132:Arm / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D001557:Benzenesulfonates; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D002144:Callithrix; D002755:Choice Behavior / Q000187:drug effects; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000008:administration & dosage*; D006439:Hemodynamics / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D007262:Infusions, Intravenous; D007698:Kinesis / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D009589:Nitrogen Oxides / Q000008:administration & dosage* / Q000097:blood; D010291:Paresis / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D010468:Perceptual Disorders / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology
D001557:Benzenesulfonates; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; C120851:disufenton sodium