NXY-059, a nitrone with free radical trapping properties inhibits release of cytochrome c after focal cerebral ischemia.
Recent studies have demonstrated that disodium 2,4-disulfophenyl-N-tert-butylnitrone (NXY-059), a novel nitrone with free radical trapping properties, has a considerable neuroprotective effect against cerebral ischemic injury. The mechanisms of its action have not been fully defined. In order to evaluate whether NXY-059 exerts its protective effects by inhibiting the release of cytochrome c, a key initiator of programmed cell death pathway, we have studied the effects of NXY-059 on reducing infarct volume and on inhibiting cytochrome c release from the mitochondria after transient focal cerebral ischemia. Wistar rats were subjected to 2 hr of middle cerebral artery occlusion and perfusion-fixed after 4, 6, 12, and 24 hr of reperfusion. NXY-059 (30 mg/kg) was i.v. injected 1 hr after reperfusion and followed immediately by 30 mg/kg/hr continuous i.v. infusion for the entire reperfusion period. The results showed that NXY-059 reduced infarct volume from 37.2% to 12.5% (p<0.0001). Immunocytochemistry demonstrated that the release of cytochrome c increased at 6 hr, peaked at 12 and 24 hr of reperfusion. NXY-059 treatment prevented ischemia-induced cytochrome c release. NXY-059 may reduce ischemic brain damage through suppressing the cell death pathway that is initiated by cytochrome c release.
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Cardiovascular Research Center, John A. Burns School of Medicine and Pacific Biomedical Research Center, University of Hawaii at Manoa, Honolulu, Biomed Tower Room T410, 1960 East-West Road, Honolulu, Hawaii 96822, USA.
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D000818:Animals; D001557:Benzenesulfonates; D016923:Cell Death; D002544:Cerebral Infarction / Q000517:prevention & control; D045304:Cytochromes c / Q000187:drug effects* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009589:Nitrogen Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion
D001557:Benzenesulfonates; D016166:Free Radical Scavengers; D009589:Nitrogen Oxides; C120851:disufenton sodium; D045304:Cytochromes c