Published Online
on August 14, 2003

A more recent version of this article appeared on September 1, 2003

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Submitted on May 16, 2003
Accepted on May 28, 2003

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; and 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.).

^* To whom correspondence should be addressed. 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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