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(Stroke. 2003;34:2228.)
© 2003 American Heart Association, Inc.

Original Contributions

Functional and Histological Evidence for the Protective Effect of NXY-059 in a Primate Model of Stroke When Given 4 Hours After Occlusion

Jonathan W.B. Marshall, PhD; Rosalyn M. Cummings; Laura J. Bowes, BA; Rosalind M. Ridley, ScD A. Richard Green, DSc

From the Medical Research Council Comparative Cognition Team, Department of Experimental Psychology, University of Cambridge, Cambridge, UK (J.W.B.M., R.M.C., L.J.B., R.M.R.), and AstraZeneca R&D Charnwood, Loughborough, UK (A.R.G.).

Correspondence to Dr Jonathan Marshall, Medical Research Council Comparative Cognition Team, Department of Experimental Psychology, University of Cambridge, Downing St, Cambridge CB2 3EB, UK. E-mail jwbm2{at}cus.cam.ac.uk

Background and Purpose— 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 µmol/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 µmol/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.

Key Words: behavior, animal • free radicals • neuroprotection • nitrogen oxides • monkeys

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