The neuroprotective efficacy of NXY-059 in permanent MCAo in the rat: Dose response and therapeutic window
Introduction. NXY-059 (disodium 4-[(tert-butylimino)methyl] benzene-1,3-disulfonate N-oxide) is a nitrone with free radical trapping properties and is being developed for the treatment of acute ischemic stroke. NXY-059 possesses proven neuroprotective efficacy in rat transient models of middle cerebral artery occlusion (MCAo) (J Cereb Blood Flow Metab 1999;19:778–87), however its efficacy in permanent models of focal cerebral ischemia has not been as extensively tested. In the present study we have examined the efficacy of NXY-059 at three doses and further examined the therapeutic window of the mid-range dose. Methods. Adult male Wistar rats (300–330g) were given a unilateral permanent MCAo using an intraluminal suture technique. To assess efficacy of three doses of NXY-059, vehicle or NXY-059 (30, 50 or 70 mg/kg/h) was infused using minipumps for 24 hours. Dosing began 5 minutes after the MCAo with a bolus injection of vehicle or NXY-059 (30, 50 or 70 mg/kg). To assess the therapeutic window, treatment with 50 mg/kg (loading dose) and 50 mg/kg/h (over 24 hours) NXY-059 was commenced at 5, 30, 60, 120 and 240 minutes after MCAo. For both assessments, brains were removed 24 hours after commencing treatment and volume of damage was calculated from 5 x 2mm sections stained with triphenyl tetrazolium chloride. Results. NXY-059 (30, 50 and 70 mg/kg/h) reduced the volume of damage by 23%, 57% and 81% respectively (p<0.05). Treatment with NXY-059 (50 mg/kg/h) beginning at 5, 30, 60, 120 and 240 minutes after permanent MCAo reduced the volumes of damage by 52%, 45%, 50%, 43% and 35% respectively (p<0.05). Conclusions. In rats given a permanent MCA occlusion, NXY-059 at doses of 30–70 mg/kg/h given for 24 hours significantly (p<0.05) reduced the volume of cerebral damage, and significant protection was seen when treatment was delayed for as long as 4 hours after permanent MCAo.