Jiancheng Zhang1,2, Li Ma1,3, Xiayun Wan1, Jiajing Shan1, Youge Qu1, Kenji Hashimoto4. 1. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan. 2. Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China. 3. Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430022, People's Republic of China. 4. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan. hashimoto@faculty.chiba-u.jp.
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.
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.
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