Functional and histological evidence for the protective effect of NXY-059 in a primate model of stroke when given 4 hours after occlusion.
OBJECTIVE
NXY-059 has substantial protective effects when administered immediately after the onset of ischemia in a primate model of stroke. This study examined the efficacy of this drug when administered 4 hours after onset, a more clinically relevant time point.


METHODS
Before surgery, marmosets were trained and tested on a number of neurological tests, which assessed general neurological function, motor ability, and spatial awareness. Four hours after permanent middle cerebral artery occlusion (pMCAO), marmosets received a bolus of saline (n=13) or NXY-059 (n=13), and osmotic minipumps were implanted, providing 48-hour saline or drug (85 micromol/kg per hour) infusion. The monkeys were retested 3 and 10 weeks after surgery. Finally, infarct size was evaluated with histological analysis.


RESULTS
The unbound plasma NXY-059 concentration was 200+/-9 micromol/L after 24-hour infusion, a concentration well tolerated in stroke patients. Drug treatment ameliorated the long-term motor impairment produced by pMCAO; the marmosets were better at using their contralesional, stroke-affected arm than controls at both 3 and 10 weeks. Saline-treated animals had a debilitating spatial neglect at 3 weeks with residual signs evident at 10 weeks. NXY-059 treatment substantially attenuated neglect at 3 weeks, with no deficit being seen at 10 weeks. NXY-059 reduced the overall infarct size by 28% (saline, 324+/-46 mm3; NXY-059, 234+/-30 mm3) with protection to the cortex, white matter, and subcortical structures.


CONCLUSIONS
NXY-059 is an effective neuroprotective agent when administered 4 hours after pMCAO in a primate species, attenuating both motor and spatial neglect. The compound also substantially lessened the volume of cerebral damage.
Marshall
Jonathan W B
JW
Medical Research Council Comparative Cognition Team, Department of Experimental Psychology, University of Cambridge, UK. jwbm2@cus.cam.ac.uk
Cummings
Rosalyn M
RM
Bowes
Laura J
LJ
Ridley
Rosalind M
RM
Green
A Richard
AR
D000818:Animals; D001557:Benzenesulfonates; D002144:Callithrix; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009589:Nitrogen Oxides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010468:Perceptual Disorders / Q000188:drug therapy / Q000209:etiology; D020127:Recovery of Function / Q000187:drug effects; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome
D001557:Benzenesulfonates; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; C120851:disufenton sodium