Dasatinib prevent hepatic fibrosis induced by carbon tetrachloride (CCl4) via anti-inflammatory and antioxidant mechanism

Abstract

SummaryObjectives: Dasatinib, a potent and broad-spectrum tyrosine kinase inhibitor, is approved for the treatment of imatinib-resistant chronic myelogenous leukemia. The aim of this study was to evaluate the anti-fibrotic, anti-inflammatory and antioxidant effects of this agent against CCl4-induced hepatic fibrosis and oxidative status.Materials and methods: Experimental fibrosis was induced in Wistar male rats by 12 weeks of CCl4 administration (i.p.). During the last 8 weeks of injection, rats were gavaged daily with Dasatinib (10 mg/kg). To evaluate anti-inflammatory and anti-fibrotic effects of Dasatinib, histopathological examination of liver tissue was performed and serum ALT and AST activities, oxidant, antioxidant parameters and hepatic tumor necrosis factor alpha (TNF-α) were examined. Moreover, transforming growth factor (TGF-β1), platelet derived growth factor (PDGF) and TNF-α mRNA expressions were also evaluated by real time polymerase chain reaction.Results: Dasatinib administration induced a significant reduction of ALT and AST activities (p < .001) and Malondialdehyde (MDA) content in CCl4 injected rats (p < .05). Concomitantly hepatic protein and mRNA expression of TNF-α, mRNA expression of TGF-β1 and PDGF were increased due to CCl4 intoxication (p < .001), but Dasatinib treatment could significantly ameliorate these mediators at the level of gene expression (p < .01) and protein level of TNF-α (p < .001). The necro-inflammatory changes in histopathological finding, nitric oxide and hydroxyproline level were also increased during 12 weeks of CCl4 administration which was significantly attenuated by Dasatinib (p < .01).Discussion and conclusion: Our findings indicate that Dasatinib can be cautiously an anti-fibrotic, anti-inflammatory and anti-oxidative agent in clinical setting.