Published online before print August 14, 2003, doi: 10.1161/01.STR.0000087790.79851.A8
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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
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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