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

Summary

Objectives: 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.

Keywords:

• Carbon tetrachloride
• Dasatinib
• liver fibrosis
• TGF-β1
• TNF-α

Acknowledgements

The authors acknowledge the Hamadan University of Medical Sciences, Hamadan, Iran for financial support. The present work was a part of the PhD thesis of A. Mohammadalipour (Project number 94011853).

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

The authors acknowledge, with thanks the Hamadan University of Medical Sciences, Hamadan, Iran for financial support (Project number 94011853).