Inhibition of the initial wave of NF-kappaB activity in rat muscle reduces ischemia/reperfusion injury.
Nuclear factor kappaB (NF-kappaB) is thought to play an important role in the 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 min to 3 h postperfusion and 6 h to 16 h postperfusion, with a decline to baseline binding activity levels between 3 h and 6 h. Inhibition of NF-kappaB activation was investigated using proline dithiocarbamate (Pro-DTC). NF-kappaB binding activity during reperfusion was significantly reduced by intravenous administration of Pro-DTC. Additionally, Pro-DTC resulted in decreased muscle edema and neutrophil activity, with an increased percentage of muscle survival compared with vehicle controls. These results demonstrate that NF-kappaB is activated during reperfusion in a biphasic manner and that the regulation of the initial phase of NF-kappaB activation affords physiological protection against a severe ischemic stress. Selective inhibition of NF-kappaB during early reperfusion may therefore be a therapeutic intervention for I/R injury.
Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287-1604, USA.
S T
ST
Lille
S R
SR
Lefler
A
A
Mowlavi
H
H
Suchy
E M
EM
Boyle
A L
AL
Farr
C Y
CY
Su
N
N
Frank
D C
DC
Mulligan
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D004195:Disease Models, Animal; D007262:Infusions, Intravenous; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D013859:Thiocarbamates / Q000008:administration & dosage
D016177:Macrophage-1 Antigen; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D011392:Proline; D017493:Leukocyte Common Antigens