Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Wright, G; Vairappan, B; Stadlbauer, V; Mookerjee, RP; Davies, NA; Jalan, R.
Reduction in hyperammonaemia by ornithine phenylacetate prevents lipopolysaccharide-induced brain edema and coma in cirrhotic rats.
Liver Int. 2012; 32(3):410-419
Doi: 10.1111/j.1478-3231.2011.02698.x
Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Stadlbauer-Köllner Vanessa
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- Abstract:
- Objective: 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-alpha (infliximab) prevent the deleterious brain consequences of lipopolysaccharide (LPS) in cirrhotic rats. Design: 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. Results: 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-alpha and IL-6 levels compared to sham. LPS significantly worsened coma stage, increased brain water and plasma and brain TNF-a. 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 NFjB. Conclusion: 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 NFjB related mechanisms.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Antibodies, Monoclonal - administration & dosage
- Bile Ducts - surgery
- Blotting, Western -
- Body Water - metabolism
- Brain - drug effects
- Brain Edema - etiology
- Cytokines - blood
- Hyperammonemia - blood
- Injections, Intraperitoneal -
- Interleukin-6 - blood
- Ligation -
- Lipopolysaccharides - toxicity
- Liver Cirrhosis - complications
- Ornithine - administration & dosage
- Rats -
- Tumor Necrosis Factor-alpha - blood
- Find related publications in this database (Keywords)
- ammonia
- cerebral edema
- hepatic encephalopathy
- inflammation
- infliximab
- L-ornithine phenylacetate
- TNF-a and astrocyte