Abstract
1. The efficacy of the free radical trapping agent NXY-059 in reducing the infarct volume following both transient and permanent focal ischaemia has been examined in rats. 2. In the transient ischaemia model, rats were subjected to a 2 h occlusion of the middle cerebral artery (MCA). Intravenous infusion of NXY-059 (1, 10 and 30 mg kg(-1) h) for 21.75 h starting 2.25 h after the occlusion, produced a dose-dependent decrease in both neurological impairment and the histologically measured infarct volume (a mean 59% decrease at 10 mg kg(-1) h). 3. In the permanent ischaemia model, animals were injected (s.c.) with a loading dose of NXY-059 of 32.5, 53.8 or 75.4 mg kg(-1) and osmotic minipumps were implanted which had been primed to deliver respectively 30, 50 or 70 mg kg(-1) h. When treatment was initiated 5 min after MCA occlusion there was a dose dependent protection of both cortical and sub-cortical tissue (cortex: 63% at the mid-range dose). Protection was related linearly to plasma concentration (plasma unbound NXY-059 concentration at 1 h: 37+/-16 micromol l(-1) at the mid-range dose). 4. When the mid range dose was administered between 5 min - 4 h after MCA occlusion, a marked and statistically significant protection was seen at all time points (44% protection in cortex at 4 h). 5. These data demonstrate the substantial neuroprotective efficacy of NXY-059 at plasma concentrations that can be achieved clinically and indicate that NXY-059 also has a therapeutic window of opportunity that is clinically relevant.