3H-1,2-dithiole-3-thione targets nuclear factor kappaB to block expression of inducible nitric-oxide synthase, prevents hypotension, and improves survival in endotoxemic rats.
Septicemia is a major cause of death associated with noncoronary intensive care. Systemic production of nitric oxide (NO) by inducible nitric-oxide synthase (iNOS) is a major cause of hypotension and poor organ perfusion seen in septic shock. Here, we show that pretreatment of F344 rats with the cancer chemoprotective agent 3H-1,2-dithiole-3-thione (D3T) blocks lipopolysaccharide (LPS)-mediated induction of hepatic iNOS and significantly reduces the associated serum levels of NO metabolites and enzyme markers of toxicity provoked by treatment with LPS. Immunohistochemical analysis shows that this protective effect is largely due to suppression of iNOS expression in hepatocytes. Importantly, pretreatment of animals with D3T blunts LPS-mediated hypotension and dramatically increases their survival. Inasmuch as iNOS expression can be regulated by nuclear factor (NF) kappaB, mechanistic studies show that D3T blocks NFkappaB nuclear translocation and DNA binding and that these effects are accompanied by changes in the levels of phospho-inhibitor of NFkappaB. In conclusion, this study identifies new drug classes and targets that may improve the prevention and treatment of septic shock, as well as chronic diseases associated with the NFkappaB and iNOS pathways.
Karuri
Asok R
AR
W. Harry Feinstone Center for Genomic Research, University of Memphis, TN 38152, USA.
Huang
Yong
Y
Bodreddigari
Sridevi
S
Sutter
Carrie Hayes
CH
Roebuck
Bill D
BD
Kensler
Thomas W
TW
Sutter
Thomas R
TR
D000818:Animals; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D024202:Electrophoretic Mobility Shift Assay; D019446:Endotoxemia / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007022:Hypotension / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D013871:Thiones / Q000627:therapeutic use*; D013876:Thiophenes / Q000627:therapeutic use*
D008070:Lipopolysaccharides; D016328:NF-kappa B; D013871:Thiones; D013876:Thiophenes; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D005978:Glutathione; C049325:1,2-dithiol-3-thione