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Yokukansan Reduces Cuprizone-Induced Demyelination in the Corpus Callosum Through Anti-inflammatory Effects on Microglia

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Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). The release of inflammatory cytokines and pro-oxidant molecules from microglia has been shown to play a key role in the pathology of MS. Thus, suppression of microglial cell activation is an attractive therapeutic option. Yokukansan, a traditional Japanese herbal medicine, has been shown to suppress microglial activity in the CNS. However, whether or not yokukansan reduces demyelination observed in the CNS during MS remains unknown. In this study, female C57BL/6 mice were fed a diet containing 0.2% cuprizone (bis-cyclohexanone oxaldihydrazone) to induce demyelination in the corpus callosum. We investigated whether or not yokukansan reduces cuprizone-induced demyelination using immunohistochemical analyses. Furthermore, we examined the in vitro anti-inflammatory effects of yokukansan on LPS-stimulated BV2 cells, a murine microglial cell line. Luxol fast blue staining and immunostaining for myelin basic protein demonstrated that yokukansan reduces demyelination of the corpora callosa of cuprizone-fed mice. In addition, yokukansan significantly decreased the number of activated microglial cells in the corpora callosa of cuprizone-fed mice. Furthermore, treatment with 500 μg/ml yokukansan suppressed the expression of interleukin-1β and inducible nitric-oxide synthase mRNA and protein in LPS-stimulated BV2 cells. These findings suggest that yokukansan reduces demyelination owing to anti-inflammatory effects on microglia. As yokukansan has few adverse effects, yokukansan has the potential to be a novel option to treat MS.

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Acknowledgements

Yokukansan was provided by Tsumura Research Laboratory, Tsumura & Co., Ibaraki, Japan. We thank for Dr. Morita, Dr. Yamamoto, Ms. Akiyama, for technical assistance. This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number JP 16k07023 and grants from the Akiyama Memorial Foundation (Yoshio Bando). Hua You is supported by the National Natural Science Foundation of China (81670180, 81711540047, 81370077, and 81001220), and the Beijing Nova Program of the Beijing Municipal Science and Technology Commission (Z171100001117091).

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  1. Tatsuhide Tanaka

    Present address: Department of Anatomy and Neuroscience, Faculty of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634–8521, Japan

Authors and Affiliations

  1. Department of Functional Anatomy and Neuroscience, Asahikawa Medical University, Midorigaoka-higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan

    Taichi Nomura, Yoshio Bando, Hua You, Tatsuhide Tanaka & Shigetaka Yoshida

  2. Affiliated Hospital of Academy of Military Medical Sciences, No.8 East Main Street, Fengtai District, 100071, Beijing, China

    Hua You

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  1. Taichi Nomura
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Nomura, T., Bando, Y., You, H. et al. Yokukansan Reduces Cuprizone-Induced Demyelination in the Corpus Callosum Through Anti-inflammatory Effects on Microglia. Neurochem Res 42, 3525–3536 (2017). https://doi.org/10.1007/s11064-017-2400-z

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