Inhibition of the initial wave of NF-kappa B activity in rat muscle reduces ischemia/reperfusion injury

Nuclear factor kappaB (NF-kappaB) is thought to play an important role in t he expression of genes expressed in response to ischemia/ reperfusion (I/R) injury. In this report, the activation of NF-kappaB in rat skeletal muscle during reperfusion following a 4-h ischemic period was studied. NF-kappaB activation displayed a biphasic pattern, showing peak activities from 30 mi n to 3 h postperfusion and 6 h to 16 h postperfusion, with a decline to bas eline binding activity levels between 3 h and 6 h. Inhibition of NF-kappaB activation was investigated using proline dithiocarbamate (Pro-DTC). NF-kap paB binding activity during reperfusion was significantly reduced by intrav enous administration of Pro-DTC. Additionally, Pro-DTC resulted in decrease d muscle edema and neutrophil activity, with an increased percentage of mus cle survival compared with vehicle controls. These results demonstrate that NF-kappaB is activated during reperfusion in a biphasic manner and that th e regulation of the initial phase of NF-kappaB activation affords physiolog ical protection against a severe ischemic stress. Selective inhibition of N F-kappaB during early reperfusion may therefore be a therapeutic interventi on for I/R injury. (C) 2001 John Wiley & Sons, Inc.