(Z)2-(5-(4-methoxybenzylidene)-2, 4-dioxothiazolidin-3-yl) acetic acid protects rats from CCl4-induced liver injury

Background and Aim: (Z)2-(5-(4-methoxybenzylidene)-2, 4-dioxothiazolidin-3-yl) acetic acid (MDA) is an aldose reductase (AR) inhibitor. Recent studies suggest that AR contributes to the pathogenesis of inflammation by affecting the nuclear factor ?B (NF-?B)-dependent expression of cytokines and chemokines and therefore could be a novel therapeutic target for inflammatory pathology. The current study evaluated the in vivo role of MDA in protecting the liver against injury and fibrogenesis caused by CCl4 in rats, and the underlying mechanisms. Methods: A single injection of CCl4 induced acute hepatitis, and repeated injections were used to induce hepatic fibrosis in rats. Therapeutic efficacy was assessed by comparison of the severity of hepatic injury and fibrosis in MDA-treated rats versus untreated controls. Results: MDA significantly protected the liver from injury by reducing the activity of serum alanine aminotransferase, and improving the histological architecture of the liver. MDA modulated NF-kB-dependent activation of inflammatory cytokines by reducing hepatic mRNA levels of tumor necrosis factor-a, interleukin-1b, inducible nitric oxide (NO) synthase and transforming growth factor-b. In addition, MDA attenuated oxidative stress by increasing the content of hepatic glutathione. These favorable changes were associated with suppressed hepatic NF-kB activation by MDA. MDA treatment improved liver fibrosis in rats that received repeated CCl4 injections. In vitro, MDA attenuated phosphorylation of IkB and activation of NF-kB, and thus prevented biosynthesis of NO in lipopolysaccharide-activated RAW264.7 cells. Conclusions: The present study suggests that AR is a novel therapeutic anti-inflammatory target for the treatment of hepatitis and liver fibrosis.