Resveratrol prevents fibrosis, NF-kappaB activation and TGF-beta increases induced by chronic CCl4 treatment in rats.
Resveratrol is a nonflavonoid polyphenol with antioxidant, anticancer and antiinflammatory properties. Moreover, it has been reported that this compound inhibits NF-kappaB, which regulates the transcription of several genes including cytokines such as the profibrogenic TGF-beta. The aim of this work was to evaluate the pharmacological effects of resveratrol on CCl(4)-induced cirrhosis in the rat. Four groups were formed: the control group that received the vehicles only; the CCl(4) group that received the toxin (0.4 g kg(-1), i.p., three times a week, for 8 weeks); the CCl(4) plus resveratrol (10 mg kg(-1), daily) group; and the resveratrol alone group. Alanine aminotransferase, alkaline phosphatase and bilirubins were increased by CCl(4), but resveratrol afforded some degree of protection. Glycogen was decreased markedly by CCl(4) and resveratrol prevented almost completely this effect. No antioxidant effect of resveratrol was observed. One of the most prominent effects was on fibrosis which increased near 5-fold (hydroxyproline) in the CCl(4) group; resveratrol preserved the content of collagen. These results were corroborated by histopathology. To elucidate the antifibrogenic mechanism of resveratrol, the activation of NF-kappaB and the production of TGF-beta were measured; in both cases CCl(4) increased them and resveratrol abolished them; however, changes in NF-kappaB were modest and did not reach statistical significance, while the increase in TGF-beta was about three fold and resveratrol decreased it under control values. Together, the present results indicate that resveratrol possesses a strong antifibrogenic effect at least in the CCl(4) model of cirrhosis. Moreover, the action mechanism is probably associated with its ability to reduce NF-kappaB activation and TGF-beta content.
Chávez
Enrique
E
Sección Externa de Farmacología, Cinvestav-IPN, Apdo Postal 14-740, México 07000, D.F. México.
Reyes-Gordillo
Karina
K
Segovia
José
J
Shibayama
Mineko
M
Tsutsumi
Victor
V
Vergara
Paula
P
Moreno
Mario G
MG
Muriel
Pablo
P
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001663:Bilirubin / Q000097:blood; D002251:Carbon Tetrachloride; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D020011:Protective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D000077185:Resveratrol; D013267:Stilbenes / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D016328:NF-kappa B; D020011:Protective Agents; D013267:Stilbenes; D016212:Transforming Growth Factor beta; D006003:Glycogen; D002251:Carbon Tetrachloride; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D005978:Glutathione; D000077185:Resveratrol; D001663:Bilirubin; D019803:Glutathione Disulfide