NXY-059, the free radical trapping nitrone-based agent, reduces hemiparesis and reduces grey and white matter damage after focal cerebral ischemia in monkeys
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<0.01) and 10 weeks (p<0.01) after surgery. NXY-059-treatment also significantly reduced spatial neglect measured 3 weeks after surgery (p<0.01) compared with the saline group. After behavioral testing was complete, histopathological analysis showed NXY-059-treated monkeys had significantly smaller infarcts than saline-treated monkeys (F (1, 10)=5.21, p<0.05). NXY-059 reduced overall infarct size by 51%, damage to the cortex was reduced by 54%, white matter by 52%, caudate by 49%, and putamen by 33% compared with saline-treated monkeys. In conclusion, NXY-059 substantially lessened the functional disability in these monkeys. This drug protects not only cortical tissue, but also white matter and subcortical structures against ischemic damage. Together these findings bode well for advancing this drug to further clinical trials for its use in acute stroke.