The influence of sorafenib on hepatic encephalopathy and the mechanistic survey in cirrhotic rats

Abstract

Sorafenib, a multikinase inhibitor that inhibits angiogenesis and carcinogenesis, has been used for patients with advanced hepatocellular carcinoma. However, sporadic cases have been reported with the development of hepatic encephalopathy (HE) after sorafenib treatment, mostly in those with cirrhosis. Liver function impairment, portal-systemic collaterals and brain oxidative stress participate in the pathogenesis of HE. The study therefore aimed to investigate the potential influences of sorafenib on HE and the relevant risk factors in cirrhotic rats. Liver cirrhosis was induced in Spraque-Dawley rats with common bile duct ligation (CBDL). CBDL rats received sorafenib 1 mg/kg/day or distilled water (DW) via oral gavage since the 15th day post surgery for 2 weeks. On the 28th day, after motor activities measurements, mean arterial pressure, portal pressure and heart rate were checked. Thereafter, cerebral cortex and cerebellum were dissected for oxidative stress study and blood was collected for liver biochemistry survey. Sorafenib significantly reduced portal pressure (22%) and collateral shunting degree (15%) in cirrhotic rats. Alanine transaminase, aspartate transaminase, total bilirubin and ammonia were similar in sorafenib- and DW-treated groups. Motor activities were not significantly altered by sorafenib. In cerebrum, the oxidant and antioxidant substances activities were not significantly different between the two groups, whereas they were divergent in cerebellum and hippocampus. By surveying three main aspects involved in the pathogenesis of HE, this study demonstrates that sorafenib does not increase the risk of HE in cirrhotic rats.