NXY-059, the free radical trapping nitrone-based agent, reduces hemiparesis and reduces grey and white matter damage after focal cerebral ischemia in monkeys

Abstract

60 There is little published evidence for protection of white matter with neuroprotective drugs in animal models of stroke, yet white matter protection may be important in achieving clinical efficacy. We have examined the effects of NXY-059, a nitrone-based free radical trapping agent, on long-term functional disability in a primate model of stroke. We also examined histopathological effects, including analyses of grey and white matter damage. Five minutes after unilateral permanent middle cerebral artery occlusion, marmosets received a 1 ml i.v. infusion of saline (n=5) or NXY-059 (28 mg/kg) (n=6) and osmotic minipumps (model 2001D) were implanted s.c. to provide continuous drug or saline infusion for 48 h. Drug-filled pumps released NXY-059 at a rate of approximately 16 mg/kg/h. The plasma unbound drug concentration at 24 h was 76.3 ± 5.7 μM, a level well tolerated in acute stroke patients. The monkeys had been trained and tested on a variety of behavioral tasks before surgery. NXY-059-treated monkeys were significantly better at reaching with their contralesional arm than were saline-treated monkeys when re-tested 3 (p