Abstract
Effective and well-tolerated anti-fibrotic drugs are currently lacking. Therefore, this study was carried out to investigate the potential anti-fibrotic effects of imatinib, nilotinib and silymarin on established hepatic fibrosis in the carbon tetrachloride (CCl
4) rat model. Male Wistar rats received intraperitoneal injections of CCl
4 twice weekly for 8
weeks, as well as daily intraperitoneal treatments of imatinib (10 and 20
mg/kg), nilotinib (10 and 20
mg/kg) and silymarin (100
mg/kg) during the last 4
weeks of CCl
4-intoxication. At the end of the study, hepatic damage was evaluated by analysis of liver function tests and hepatic oxidative stress parameters. Hepatic fibrosis was evaluated by histopathology and morphometry, as well as collagen and 4-hydroxyproline contents. Nilotinib (20
mg/kg) was the most effective treatment to counteract CCl
4-induced hepatic injury as indicated by liver function tests and histopathology. Nilotinib (10
mg/kg), nilotinib (20
mg/kg) and silymarin (100
mg/kg) treatments reduced the mean score of hepatic fibrosis by 31%, 68% and 47%, respectively, and hepatic collagen content by 47%, 49% and 18%, respectively in CCl
4-treated rats. Hepatic morphometric evaluation and 4-hydroxyproline content revealed that CCl
4-induced fibrosis was ameliorated significantly by nilotinib (20
mg/kg) and imatinib (20
mg/kg). Unlike nilotinib, imatinib (20
mg/kg) showed some sort of hepatic injury evidenced by elevation of serum aminotransferases and total bilirubin levels, and hepatic total nitrate/nitrite content, as well as characteristic anisonucleosis visualized with the hematoxylin-eosin staining. In conclusion, this study provides the evidence that nilotinib exerts anti-fibrotic activity and suggests that it may be valuable in the treatment of hepatic fibrosis in humans.
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► The anti-fibrotic effects of imatinib, nilotinib and silymarin were compared. ► These effects were evaluated on CCl
4-induced hepatic fibrosis in rats. ► Nilotinib was found to possess potent anti-fibrotic activity. ► In addition, nilotinib did not show any signs of hepatotoxicity. ► Thus, nilotinib may be valuable in the treatment of hepatic fibrosis in humans.