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

• Published in: Journal of cerebral blood flow and metabolism 1999-07, Vol.19 (7), p.778-787
• Main Authors: Kuroda, Satoshi, Tsuchidate, Ryoichi, Smith, Maj-Lis, Maples, Kirk R., Siesjö, Bo K.
• Format: Article
• Language: English
• Subjects: Animals; Benzenesulfonates; Biological and medical sciences; Blood-Brain Barrier; Dose-Response Relationship, Drug; Ischemic Attack, Transient - drug therapy; Ischemic Attack, Transient - pathology; Ischemic Attack, Transient - physiopathology; Male; Medical sciences; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - pharmacokinetics; Neuroprotective Agents - therapeutic use; Nitrogen Oxides - administration & dosage; Nitrogen Oxides - pharmacology; Nitrogen Oxides - therapeutic use; Pharmacology. Drug treatments; Rats; Rats, Wistar
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1097/00004647-199907000-00008

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.