Background: Ammonia is central in the pathogenesis of hepatic encephalopathy (HE) and clinical sequelae are exacerbated by systemic inflammation. Sequestration of ammonia in the gut represents a primary treatment target for HE. AST-120 (spherical carbon adsorbent), an oral adsorbent of engineered activated carbon microspheres with surface areas exceeding 1600m2/g works as a sink for neuro- and hepato–toxins present in the gut. In this study, we evaluated the capacity of AST-120 to lower arterial ammonia, brain edema and systemic inflammatory markers in cirrhotic rats. Methods: Cirrhosis was induced in rats by bile duct ligation (BDL). BDL and SHAM-operated rats received AST-120 dispersed in methylcellulose by gavage at a dose of 0.1, 1 or 4g/kg/day for 6 weeks. Ammonia and the pro-inflammatory cytokine TNF-α were measured in arterial plasma using a commercially available kit and ELISA technique respectively. Brain water content was measured in the frontal cortex, cerebellum and brain stem using the specific gravimetric technique. Results: Arterial ammonia increased in non-treated BDL vs SHAM-operated controls (166.9±21.1uM vs 70.5±14.4uM, p<0.01). All doses of AST-120 decreased ammonia in BDL to similar levels found in respective SHAM-operated controls; 0.1g/kg/day (117.2±12.6uM vs 100.4±7.3uM, p>0.05); 1g/kg/day (78.9±22.3uM vs 78.1±8.9uM, p>0.05) and 4g/kg/day (48.8±19.6uM vs 49.9±14.7uM, p>0.05). Ammonia levels significantly correlated with doses of AST-120 (r=-0.66, p<0.0001). Brain water content increased in frontal cortex, cerebellum and brain stem in BDL vs SHAM-operated and was normalized in all AST-120 treatment groups compared to respective controls. Circulating levels of TNF-α were significantly increased in BDL vs SHAM-operated rats (p<0.05). AST-120 treatment did not attenuate TNF-α levels compared to respective SHAM-operated controls. Conclusion: AST-120 treatment dose-dependently decreased arterial ammonia levels, which resulted in normalization of multi-foci brain edema. This response was not correlated with differences in levels of circulating TNF-α. AST-120 treatment is a safe, non-antibiotic alternative demonstrating a significant ammonia-lowering effects, as well as a protective effect on the development of brain edema in rats with chronic liver disease. AST-120 represents a useful tool to elucidate further the relationship between circulating ammonia and gut-derived or systemic inflammatory components of liver disease.
