The antioxidant activity of chondroitin‐4‐sulphate, in carbon tetrachloride‐induced acute hepatitis in mice, involves NF‐κB and caspase activation

• Published in: British journal of pharmacology 2008-11, Vol.155 (6), p.945-956
• Main Authors: Campo, G M, Avenoso, A, Campo, S, Nastasi, G, Traina, P, D'Ascola, A, Rugolo, C A, Calatroni, A
• Format: Article
• Language: English
• Subjects: antioxidants; carbon tetrachloride; caspases; chondroitin‐4‐sulphate; free radicals; liver damage; NF‐κB; oxidative stress; Research Papers
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/bjp.2008.338

Background and purpose: Reactive oxygen species (ROC) are the main causes of carbon tetrachloride (CCl4)‐induced acute liver injury. Chondroitin‐4‐sulphate (C4S) is known to inhibit lipid peroxidation through antioxidant mechanisms. Activation of nuclear factor (NF)‐κB and caspases may strongly intensify inflammation and cell damage, in addition to that directly exerted by ROS. We investigated whether treatment with C4S, besides exerting antioxidant activity, was able to modulate NF‐κB and apoptosis activation in CCl4‐induced liver injury in mice. Experimental approach: Acute hepatitis was induced in mice by an i.p. injection of CCl4. Varying doses of C4S were administered i.p. 1 h before, 6 and 12 h after CCl4 injection. 24 h after CCl4 injection, the mice were killed for biochemical and histological analysis. Key results: CCl4 injection produced: marked elevation of alanine aminotransferase and aspartate aminotransferase; hepatic membrane lipid peroxidation, assayed by 8‐isoprostane levels; and depletion of reduced glutathione and superoxide dismutase. CCl4 also decreased NF‐κB translocation and IkBα, and increased gene expression of mRNA and protein of metalloproteases (MMP)‐2 and ‐9, and of pro‐ and cleaved forms of caspases‐3 and ‐7. There was also increased liver polymorphonuclear infiltration, evaluated by elastase assay, and hepatic cell disruption. C4S treatment inhibited lipid peroxidation; blocked NF‐κB activation and IkBα protein loss; decreased mRNA and proteins for MMPs and caspases; restored endogenous antioxidants; limited hepatic polymorphonuclear accumulation and tissue damage. Conclusions and implications: As antioxidants may inhibit NF‐κB and caspase activation, we hypothesize that treatment with C4S was able to inhibit NF‐κB and apoptosis activation in hepatic injury. British Journal of Pharmacology (2008) 155, 945–956; doi:10.1038/bjp.2008.338; published online 25 August 2008