Hyperammonemia increases sensitivity to LPS.
Metabolic and cognitive alterations occur during hyperammonemia. Here, we report that chronic hyperammonemia also leads to increased sensitivity to LPS. Sparse-fur mice were challenged i.p. with LPS or saline control and then tested for motivation to investigate a novel juvenile over 24 h. Cytokine, ammonia, and urea concentration were quantified at the peak of sickness (2 h post injection). Chronic hyperammonemic Otc(spf-ash) mice displayed more pronounced and prolonged sickness behavior in response to LPS (P=0.02). LPS significantly (P<0.0001) increased plasma concentrations of TNFalpha, IL-1 beta, IL-6, IL-15, IL-9, IL-2, IL-1 alpha, IL-1 beta, Rantes, MIP1 alpha, MIP1 beta, MCP-1, KC, GM-CSF, G-CSF, Eotaxin, IL-13, and IL-12 in both wild type and Otc(spf-ash) mice. No significant genotype/treatment interactions (P>0.1) were detected for any cytokine. Adult Otc(spf-ash) mice (168+/-41 microM) had four times higher plasma ammonia compared to wild type mice (40 +/- 6 microM) (P=0.002). Two hours after LPS injection, plasma ammonia concentrations tended (P=0.08) to decrease in both wild type and Otc(spf-ash) mice. Learning and memory behaviors were assessed in mice under basal conditions to determine the impact of chronic hyperammonemia on cognition. Otc(spf-ash) mice performed significantly poorer in the two trial Y-maze (P=0.02) and the Morris water maze (P=0.001) than their littermate wild type controls. Taken together, these data indicate that chronic hyperammonemia results in impaired cognition and creates a state of LPS hypersensitivity.
Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Juan C
JC
Marini
Suzanne R
SR
Broussard
D000818:Animals; D001288:Attention / Q000502:physiology; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D022124:Hyperammonemia / Q000097:blood / Q000276:immunology* / Q000523:psychology*; D007249:Inflammation; D008070:Lipopolysaccharides / Q000276:immunology*; D008297:Male; D018782:Maze Learning; D008568:Memory / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D020163:Ornithine Carbamoyltransferase Deficiency Disease; D012919:Social Behavior; D013047:Specific Pathogen-Free Organisms
D016207:Cytokines; D008070:Lipopolysaccharides