Reduction in hyperammonaemia by ornithine phenylacetate prevents lipopolysaccharide‐induced brain edema and coma in cirrhotic rats

Abstract

In liver failure, inflammation synergistically exacerbates the deleterious cerebral effects of ammonia. The aims were to test whether treatment with the ammonia-lowering agent ornithine phenylacetate (OP) and/or anti-TNF-α (infliximab) prevent the deleterious brain consequences of lipopolysaccharide (LPS) in cirrhotic rats. Rats 4 weeks following bile duct-ligation (BDL), sham-operation (sham) and/or 7 days hyperammonemic feed (HD), were randomized to receive LPS (1 mg/kg) or saline, and treatment with either 3 days intraperitoneal injections of OP (0.6 g/kg) and/or infliximab, 10 mg/kg. Animals were sacrificed at coma stages or at 3 h. In sham rats, both HD and LPS increased brain water, with an increase in ammonia in the former and brain cytokines in the latter but with no effect on consciousness. BDL + HD rats caused significantly higher plasma ammonia, TNF-α and IL-6 levels compared to sham. LPS significantly worsened coma stage, increased brain water and plasma and brain TNF-α. OP significantly delayed LPS-induced progression to coma stages (P < 0.009), reduced arterial ammonia and brain water (P < 0.001 and P < 0.01 respectively), which was associated with a significant reduction in cytokines. Infliximab significantly reduced plasma and brain cytokines, but not brain water. OP + infliximab attenuated increase in brain water and delayed occurrence of coma, which was not different to OP alone. In BDL rats, OP reduced the expression of brain iNOS and NFκB. Reduction in ammonia with OP in cirrhotic rats prevents LPS-induced brain edema and delays coma, suggesting that ammonia may prime the brain to the deleterious effect of LPS, possibly through effects on iNOS and NFκB related mechanisms.