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.
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Data Availability
The datasets analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- ELISA :
-
Enzyme-linked immunosorbent assay
- Iba-1 :
-
Ionized calcium-binding adapter molecule 1
- IFN :
-
Interferon
- IL :
-
Interleukin
- iNOS :
-
Inducible nitric oxide synthase
- LPS :
-
Lipopolysaccharide
- NMDAR :
-
N-Methyl-d-aspartate receptor
- PFC :
-
Prefrontal cortex
- TNF-α :
-
Tumor necrosis factor-α
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This study was supported by grant from Japan Agency for Medical Research and Development (AMED) (to K.H., JP20dm0107119).
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KH worked on experimental design. JCZ, LM, XYW, JJS, and YGQ performed the experiments. JCZ analyzed the data. KH and JCZ contributed to the writing of the manuscript. All authors read and approved the final manuscript.
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All animal experiments were carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health, USA, and approved by the Chiba University Institutional Animal Care and Use Committee (permission number: 2–308).
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Dr. Hashimoto is the inventor of filed patent applications on “The use of R-ketamine in the treatment of psychiatric diseases,” “(S)-norketamine and salt thereof as pharmaceutical,” “R-ketamine and derivative thereof as prophylactic or therapeutic agent for neurodegeneration disease or recognition function disorder,” “Preventive or therapeutic agent and pharmaceutical composition for inflammatory diseases or bone diseases,” and “R-ketamine and its derivatives as a preventive or therapeutic agent for a neurodevelopmental disorder” by the Chiba University. Dr. Hashimoto also declares that he has received research support and consultant from Dainippon Sumitomo, Otsuka, and Taisho. The other authors have no conflict of interest.
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Jiancheng Zhang and Li Ma contributed equally to this work.
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Zhang, J., Ma, L., Wan, X. et al. (R)-Ketamine attenuates LPS-induced endotoxin-derived delirium through inhibition of neuroinflammation. Psychopharmacology 238, 2743–2753 (2021). https://doi.org/10.1007/s00213-021-05889-6
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DOI: https://doi.org/10.1007/s00213-021-05889-6