Neuroprotective Effects of a Novel Nitrone, NXY-059, after Transient Focal Cerebral Ischemia in the Rat

Abstract

Recent results have demonstrated that the spin trapping agent α-phenyl- N- tert-butyl nitrone (PBN) reduces infarct volume in rats subjected to 2 hours of middle cerebral artery occlusion, even when given 1 to 3 hours after the start of recirculation. In the current study, the authors assessed the effect of NXY-059, a novel nitrone that is more soluble than PBN. Loading doses were given of 0.30, 3.0, or 30 mg · kg⁻¹ followed by 0.30, 3.0, or 30 mg · kg⁻¹ · h⁻¹ for 24 or 48 hours. Dose–response studies showed that when treatment was begun 1 hour after recirculation, 0.30 mg · kg⁻¹ had a small and 30 mg · kg-i a marked effect on infarct volume. At equimolar doses (3.0 mg · kg⁻¹ for NXY-059 and 1.4 mg · kg⁻¹ for PBN), NXY-059 was more efficacious than PBN. Similar results were obtained when a recovery period of 7 days was allowed. The window of therapeutic opportunity for NXY-059 was 3 to 6 hours after the start of recirculation. Studies of the transfer constant of [¹⁴C]NXY-059 showed that, in contrast to PBN, this more soluble nitrone penetrates the blood-brain barrier less extensively. This fact, and the pronounced antiischemic effect of NXY-059, suggest that the delayed events leading to infarction may be influenced by reactions occurring at the blood–endothelial interface.