NXY-059, a nitrone with free radical trapping properties inhibits release of cytochrome c after focal cerebral ischemia

Cell Mol Biol (Noisy-le-grand). 2003 Dec;49(8):1249-52.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Benzenesulfonates
  • Cell Death
  • Cerebral Infarction / prevention & control
  • Cytochromes c / drug effects*
  • Cytochromes c / metabolism
  • Free Radical Scavengers / pharmacology
  • Free Radical Scavengers / therapeutic use
  • Ischemic Attack, Transient / drug therapy*
  • Male
  • Mitochondria / drug effects
  • Mitochondria / pathology
  • Nitrogen Oxides / pharmacology*
  • Nitrogen Oxides / therapeutic use
  • Rats
  • Rats, Wistar
  • Reperfusion

Substances

  • Benzenesulfonates
  • Free Radical Scavengers
  • Nitrogen Oxides
  • disufenton sodium
  • Cytochromes c