Comparison of imatinib, nilotinib and silymarin in the treatment of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis

ME Shaker, KR Zalata, WZ Mehal, GE Shiha… - Toxicology and applied …, 2011 - Elsevier
Toxicology and applied pharmacology, 2011Elsevier
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 (CCl4) rat model. Male Wistar rats
received intraperitoneal injections of CCl4 twice weekly for 8weeks, as well as daily
intraperitoneal treatments of imatinib (10 and 20mg/kg), nilotinib (10 and 20mg/kg) and
silymarin (100mg/kg) during the last 4weeks of CCl4-intoxication. At the end of the study …
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 (CCl4) rat model. Male Wistar rats received intraperitoneal injections of CCl4 twice weekly for 8weeks, as well as daily intraperitoneal treatments of imatinib (10 and 20mg/kg), nilotinib (10 and 20mg/kg) and silymarin (100mg/kg) during the last 4weeks of CCl4-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 (20mg/kg) was the most effective treatment to counteract CCl4-induced hepatic injury as indicated by liver function tests and histopathology. Nilotinib (10mg/kg), nilotinib (20mg/kg) and silymarin (100mg/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 CCl4-treated rats. Hepatic morphometric evaluation and 4-hydroxyproline content revealed that CCl4-induced fibrosis was ameliorated significantly by nilotinib (20mg/kg) and imatinib (20mg/kg). Unlike nilotinib, imatinib (20mg/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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