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Yokukansan suppresses neuroinflammation in the hippocampus of mice and decreases the duration of lipopolysaccharide- and diazepam-mediated loss of righting reflex induced by pentobarbital

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Abstract

Neuroinflammation is associated with the development of hypoactive delirium, which results in poor clinical outcomes. Drugs effective against hypoactive sur have not yet been established. Yokukansan has an anti-neuroinflammatory effect, making it potentially effective against hypoactive delirium. This study aimed to examine the effect of Yokukansan on the pentobarbital-induced loss of righting reflex duration extended with lipopolysaccharide (LPS)-induced neuroinflammation and diazepam-induced gamma-aminobutyric acid receptor stimulation in a mouse model. The active ingredients in Yokukansan and its anti-neuroinflammatory effect on the hippocampus were also investigated. Furthermore, we examined the in vitro anti-inflammatory effects of Yokukansan on LPS-stimulated BV2 cells, a murine microglial cell line. Findings revealed that treatment with Yokukansan significantly decreased the duration of pentobarbital-induced loss of righting reflex by attenuating the LPS-induced increase in interleukin-6 and tumor necrosis factor-alpha levels in the hippocampus. Moreover, treatment with Yokukansan significantly decreased the number of ionized calcium-binding adapter molecule-1-positive cells in the hippocampal dentate gyrus after 24 h of LPS administration. In addition, glycyrrhizic acid, an active ingredient in Yokukansan, partially decreased the duration of pentobarbital-induced loss of righting reflex. Treatment with Yokukansan also suppressed the expression of inducible nitric oxide, interleukin-6, and tumor necrosis factor mRNA in LPS-stimulated BV2 cells. Thus, these findings suggest that Yokukansan and glycyrrhizic acid may be effective therapeutic agents for treating neuroinflammation-induced hypoactive delirium.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Material availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank Soichiro Ushio for his advice on experimental design.

Funding

This work was supported by MEXT/JSPS KAKENHI [Grant number 20H01008].

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Authors and Affiliations

  1. Graduate School of Integrated Arts and Sciences, Kochi University, 185-1 Kohasu, Oko-cho, Nankoku-shi, Kochi, Japan

    Kei Kawada, Shumpei Morisawa, Tetsushi Kawazoe, Motoki Nishida, Satomi Nishimura, Naohisa Tamura & Mitsuhiko Miyamura

  2. Department of Pharmacy, Kochi Medical School Hospital, 185-1 Kohasu, Oko, Nankoku, Kochi, Japan

    Kei Kawada, Tomoaki Ishida, Kohei Jobu, Shumpei Morisawa, Tetsushi Kawazoe, Motoki Nishida, Satomi Nishimura, Naohisa Tamura, Saburo Yoshioka & Mitsuhiko Miyamura

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  1. Kei Kawada
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Contributions

KK: conceptualization, methodoloigy, Investigation, writing—original Draft, project administration, funding acquisition. TI: conceptualization, methodology, formal analysis, investigation, writing—review and editing. KJ: validation, investigation, resources, writing—review and editing. SM: investigation. TK: investigation. MN: investigation. SN: investigation. NT: investigation. SY: investigation, data curation. MM: resources, writing—review and editing, supervision.

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Correspondence to Kei Kawada.

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The authors have no competing interests to declare that are relevant to the content of this article.

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Animal experiments were conducted with approval from the Kochi University Animal Experiment Ethics Committee (approval no. N-00028, July 30, 2020).

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Kawada, K., Ishida, T., Jobu, K. et al. Yokukansan suppresses neuroinflammation in the hippocampus of mice and decreases the duration of lipopolysaccharide- and diazepam-mediated loss of righting reflex induced by pentobarbital. J Nat Med 76, 634–644 (2022). https://doi.org/10.1007/s11418-022-01612-7

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