Nilotinib counteracts thioacetamide‐induced hepatic oxidative stress and attenuates liver fibrosis progression

Abstract

The aim of this study was to evaluate and compare the effects of imatinib and nilotinib to that of silymarin on established liver fibrosis and oxidative stress in a thioacetamide (TAA) rat model. Male Wistar rats received intraperitoneal (i.p.) injections of TAA (150mg/kg, twice weekly) for 12weeks. Daily treatments with imatinib (10mg/kg), nilotinib (10mg/kg), and silymarin (100mg/kg) were administered orally during the last 4weeks of TAA-administration. At the end of the study, hepatic damage was evaluated by analysis of liver function tests in serum. Hepatic histopathology and collagen content were employed to quantify liver fibrosis. Hepatic oxidative stress was assessed by measuring malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), total nitrate/nitrite (NOx), and reduced glutathione (GSH) contents, as well as myeloperoxidase (MPO) and superoxide dismutase (SOD) activities. Nilotinib, silymarin and, to a lesser extent, imatinib treatments ameliorated TAA-induced hepatic oxidative stress and damage as indicated by hepatic MDA, 4-HNE, NOx, GSH, MPO and SOD levels, as well as liver function tests. Hepatic histopathology results revealed that nilotinib, imatinib, and silymarin treatments decreased the mean score of fibrosis in TAA-treated rats by 24, 14, and 3%, respectively. However, nilotinib and silymarin, but not imatinib, treatments decreased hepatic collagen content in TAA-treated rats by 17 and 36%, respectively. In conclusion, we demonstrated for the first time that nilotinib not only protected against hepatic oxidative stress, but also slowed down liver fibrosis progression. Thus, we provide the first evidence that nilotinib might be a promising anti-fibrotic drug.

Hepatoprotective effect of oral application of a silymarin extract in carbon tetrachloride-induced hepatotoxicity in rats

“…SE treatment reduced the CCl 4 -induced expression of TGF-β and collagen-I which play crucial roles in liver fibrosis also in the CCl 4 model [6,7,9,16]. In our study, a remarkable decrease of pro-fibrogenic and pro-inflammatory mRNAs was observed, leading to the conclusion that the used silymarin extract has protective effects on the formation of fibrosis after acute liver injury induced by models of liver injury [2,4,14,21,23]. The protective role of silymarin extract on early stages of fibrosis and liver damage -as shown in this study -may also be relevant in chronic liver disease.…”

“…Although, the chemical agents showed a profound anti-fibrotic potential, they exhibited marked toxicity on hepatocytes. The advantage of milk thistle treatment was that no toxic side effects on the liver were observed [21]. Also in our study we did not observe any negative side effects in SE-treated rats (data not shown).…”

Combination Therapy with Taurine, Epigallocatechin Gallate and Genistein for Protection against Hepatic Fibrosis Induced by Alcohol in Rats

“…Lipid peroxidation in the liver was determined by measuring the level of malondialdehyde (MDA), an end product of lipid peroxidation, using a thiobarbiturate method. 20) The level of hepatic MDA was expressed as µmol/g protein.…”

Nilotinib Attenuates Renal Injury and Prolongs Survival in Chronic Kidney Disease

“…10 -13 Thus, it is presumable that nilotinib has beneficial effects in renal diseases comparable to imatinib. Although nilotinib has shown efficacy in models of liver fibrosis and oxidative stress in a thioacetamide rat model compared with imatinib, 14 the effects of nilotinib on experimental models of renal disease have not yet been reported.…”