(R)-Ketamine attenuates LPS-induced endotoxin-derived delirium through inhibition of neuroinflammation

Abstract

Rationale: (R)-Ketamine produced beneficial effects in a variety of models of inflammatory diseases, including low dose of bacterial lipopolysaccharide (LPS) (0.5-1.0 mg/kg)-induced endotoxemia. LPS-treated mice have been used as animal model of delirium.

Objectives: We investigated the effects of (R)-ketamine in neuroinflammation and cognitive impairment in rodents after administration of high dose of LPS.

Methods: LPS (5 mg/kg) or saline was administered intraperitoneally (i.p.) to mice. (R)-Ketamine (10 mg/kg) was administrated i.p. 24 h before and/or 10 min after LPS injection.

Results: LPS (5.0 mg/kg) caused a remarkable splenomegaly and increased plasma levels of pro-inflammatory cytokines [i.e., interleukin (IL-6), IL-17A, and interferon (IFN)-γ]. There were positive correlations between spleen weight and plasma cytokines levels. Furthermore, LPS led to increased levels of pro-inflammatory cytokines in the prefrontal cortex (PFC) and hippocampus. Moreover, LPS impaired the natural and learned behaviors, as demonstrated by a decrease in the number of mice's entries and duration in the novel arm in the Y maze test and an increase in the latency of mice to eat the food in the buried food test. Interestingly, the treatment with (R)-ketamine (twice 24 h before and 10 min after LPS injection) significantly attenuated LPS-induced splenomegaly, central and systemic inflammation, and cognitive impairment.

Conclusion: Our results highlighted the importance of combined prophylactic and therapeutic use of (R)-ketamine in the attenuation of LPS-induced systemic inflammation, neuroinflammation, and cognitive impairment in mice. It is likely that (R)-ketamine could be a prophylactic drug for delirium.

Keywords: (R)-Ketamine; Cognition; LPS; Neuroinflammation.