Evaluation of the role of TLR4 in endotoxin-induced hepatic encephalopathy in rats with biliary cirrhosis

Hepatic encephalopathy is defined as a neuropsychiatric brain dysfunction in acute or chronic liver failure. Infection and inflammation have crucial role in its pathophysiology. The purpose of our study was to demonstrate the relationship between toll-like receptor 4 (TLR4) expression and the encephalopathy induced with endotoxin in biliary cirrhotic rats.

The present study was conducted experimentally on male adult Wistar albino rats from May to January 2018 at the Pharmacology Department of Medical Faculty, Tehran University of Medical Sciences, Tehran, Iran. The animals were divided into two groups, cirrhotic vs sham-operated. Cirrhosis was induced by surgical ligation of the bile duct in male Wistar rats but in sham group the bile duct was not ligated during abdominal surgery (control). The animals in each group were divided to two subgroups that half of them were given intraperitoneally saline or low dose of endotoxin (0.1 mg/kg) on day 29. Then animal behavior study was done on the clinical sign of hepatic encephalopathy. Also, the histopathology of brain cortex and the expression of brain cortex toll-like receptor four protein were evaluated.

Our results showed that endotoxin treatment decreased the patient's level of alertness and produced hepatic encephalopathy signs in cirrhotic rats and control groups. Cirrhosis increases toll-like receptor four expression in brain and acute endotoxin treatment increases toll-like receptor four expression in this group still more. It means that acute endotoxin treatment-induced clinical signs of acute encephalopathy in sham and cirrhotic rats and significant toll-like receptor four overexpression in cirrhotic animals. The histopathological assessment did not show a significant difference between the groups and did not show any changes after induction of cirrhosis and/or acute endotoxin treatment.

Cirrhosis and acute low dose endotoxin injection in cirrhotic rats induced hepatic encephalopathy signs that parallels with significant increased toll-like receptor 4 protein expression in brain cortex. Since the severity of the signs of encephalopathy was the same as intact animals, based on the definitions in pharmacology, in the cells of cirrhotic groups endotoxin tolerance has developed.