UPDATE ON PATHOPHYSIOLOGIC MECHANISMS OF THIOACETAMIDE -INDUCED HEPATIC ENCEPHALOPATHY

Abstract

Hepatic encephalopathy (HE) is a neuropsychiatric complication of cirrhosis. Ammonia is recognized as a crucial component in the pathogenesis of HE, but many other factors are also implicated in the development of the disease. The precise pathophysiologic mechanisms behind hepatic encephalopathy induced by Thioacetamide have not been understood fully. Thus, the present study was constructed to explore the underlying pathophysiologic mechanisms of Thioacetamide -induced hepatic encephalopathy in the experimental animals. For the present study, forty adult male albino rats of Wistar strain were divided into four groups. They were labelled namely group (1) control group (3 days), group (2) Thioacetamide group (3 days), and group (3) control group (3 months) and group (4) Thioacetamide group (3 months). Relevant biochemical markers represented in serum liver enzymes activity, total protein, albumin and bilirubin levels were detected. Serum, liver and brain ammonia concentration was determined. Oxidant/ antioxidant status of liver and brain was assessed. Serum inflammatory mediators like TNF-α and S100β were evaluated. Moreover, the histopathological investigation of liver and brain tissue sections was performed. Our results revealed that Thioacetamide produced significant elevation in serum liver enzymes (ALT and AST) activity, total bilirubin level in concomitant with significant depletion in serum total protein and albumin levels. In addition, Thioacetamide caused significant increase in serum, liver and brain ammonia concentration. Moreover, Thioacetamide could significantly elevate liver and brain malondialdehyde and nitric oxide content and suppress liver and brain antioxidant enzymes (GPX and SOD) activity. Furthermore, Thioacetamide elicited significant increase in serum TNF-α and S100β levels in a time dependent manner versus the corresponding control group. Optical micrograph of a cross-sectioned liver and brain tissues showed hepatic fibrosis and haemorrhage with diffuse gliosis in the cerebrum area of the brain. These findings indicate that the devastating effect of Thioacetamide seems to depend on generation of hyperammonia, perturbation of Oxidant/ antioxidant homeostasis leading to imbalance in cellular functions, triggering inflammatory cascade and alteration of liver and brain tissue architecture. Thus, Thioacetamide offers multimechanistic approach to induce hepatic encephalopathy in the experimental animals.