Proanthocyanidin protects against cisplatin-induced oxidative liver damage through inhibition of inflammation and NF-κß/TLR-4 pathway.

ABSTRACT

Although cisplatin (CIS) is a highly effective anticancer drug, hepatotoxicity is one of the most common adverse effects associated with its use. Recently, reactive oxygen species (ROS) and inflammation are suggested to be key factors in the pathophysiology of CIS-induced acute liver damage. The aim of this study is to investigate the possible protective effect of proanthocyanidin (PRO) against CIS-induced acute hepatotoxicity. Rats were divided into four groups 1, Control; 2, PRO; 3, CIS; and 4, PRO + CIS. Biochemical studies and histopathology were used to assess liver damage. ROS, inflammatory cytokines, nuclear factor kappa beta (NF-κß), inducible cyclooxygenase enzyme (COX-2), inducible nitric oxide synthase (iNOS), toll-like receptor-4 (TLR-4) gene expression, and apoptotic markers were also assessed. PRO pretreatment protected the liver against CIS-induced toxicity as indicated by decreased plasma levels of liver function enzymes and the normal liver histopathology observed in the PRO + CIS group. PRO pretreatment also diminished indicators of oxidative stress in the liver, including nitric oxide (NO) and malondialdehyde (MDA). It also increased the antioxidants, reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) in the liver. Plasma interleukin-1 beta (IL-1ß), IL-6, and tumor necrosis factor-alpha (TNF-α) were all reduced. Liver gene expression of NF-κß, COX-2, iNOS, and TLR-4 were all downregulated. Furthermore, PRO administration downregulated the liver expression of the apoptotic marker, Bax, while upregulated the antiapoptotic marker, Bcl2. In conclusion, our results revealed that PRO may protect against CIS-induced acute liver damage mainly through inhibition of ROS, inflammation, and apoptosis.