Dimethylfumarate ameliorates hepatic injury and fibrosis induced by carbon tetrachloride

Abstract

The current study was designed to assess the antifibrotic effect of dimethylfumarate (DMF) on CCl₄-induced hepatic injury in rats. Hepatic injury was induced by intraperitoneal twice weekly injection of CCl₄ for 2 and 3 months. DMF was administered orally during the last 4 weeks in each model. Liver injury was estimated using biochemical parameters such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), total serum bilirubin (TSB), total protein, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). Additionally, oxidative stress parameters such as superoxide dismutase (SOD), reduced glutathione (GSH), nitric oxide (NOx), and malondialdehyde (MDA) were studied. Collagen IV (Col IV), alpha-smooth muscle actin (α-SMA), transforming growth factor beta1 (TGF-β1) and nuclear factor kappa B (NF-κB) were also assessed as markers of fibrosis and inflammation. Histopathological examination of liver tissues was performed and compared with control. The obtained results showed that DMF ameliorated the elevated markers of liver injury and oxidative stress in addition to hepatic necroinflammation scoring induced by CCl₄. Furthermore, DMF ameliorated CCl₄-induced fibrosis as evidenced by histopathological scoring and collagen IV content. Besides, we investigated the possible underlying mechanisms for these effects which include: (1) attenuating oxidative stress as designated by decreased MDA and NOx as well as increased GSH and SOD levels; (2) anti-inflammatory effect as evidenced by inhibitory effect on NF-κB; (3) preventing hepatic stellate cells (HSCs) activation as indicated by blunting the expression of α-SMA; and (4) downregulating the fibrogenesis response of HSCs as denoted by inhibiting TGF-β1 secretion and Col IV deposition. In conclusion, this study clarified the antifibrotic effect of DMF that might serve as a new candidate for management of liver fibrosis.

Keywords: Carbon tetrachloride; Dimethylfumarate; Hepatic fibrosis.