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 alpha-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 x kg(-1) followed by 0.30, 3.0, or 30 mg x kg(-1) x h(-1) for 24 or 48 hours. Dose-response studies showed that when treatment was begun 1 hour after recirculation, 0.30 mg x kg(-1) had a small and 30 mg x kg(-1) a marked effect on infarct volume. At equimolar doses (3.0 mg x kg(-1) for NXY-059 and 1.4 mg x 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.

• Authors: S Kuroda, R Tsuchidate, M L Smith, K R Maples, B K Siesjö
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 19 Issue 7 Pg. 778-87 (Jul 1999) ISSN: 0271-678X [Print] United States
• PMID: 10413033 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzenesulfonates
• Neuroprotective Agents
• Nitrogen Oxides
• nitrones
• disufenton sodium

Topics

• Animals
• Benzenesulfonates
• Blood-Brain Barrier
• Dose-Response Relationship, Drug
• Ischemic Attack, Transient (drug therapy, pathology, physiopathology)
• Male
• Neuroprotective Agents (administration & dosage, pharmacokinetics, therapeutic use)
• Nitrogen Oxides (administration & dosage, pharmacology, therapeutic use)
• Rats
• Rats, Wistar