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 Otcspf-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 TNFα, IL-1β, IL-6, IL-15, IL-9, IL-2, IL-1α, IL-1β, Rantes, MIP1α, MIP1β, MCP-1, KC, GM-CSF, G-CSF, Eotaxin, IL-13, and IL-12 in both wild type and Otcspf-ash mice. No significant genotype/treatment interactions (P > 0.1) were detected for any cytokine. Adult Otcspf-ash mice (168 ± 41 μM) had four times higher plasma ammonia compared to wild type mice (40 ± 6 μM) (P = 0.002). Two hours after LPS injection, plasma ammonia concentrations tended (P = 0.08) to decrease in both wild type and Otcspf-ash mice. Learning and memory behaviors were assessed in mice under basal conditions to determine the impact of chronic hyperammonemia on cognition. Otcspf-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.