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Novel anti-inflammatory agent 3-[(dodecylthiocarbonyl)-methyl]-glutarimide ameliorates murine models of inflammatory bowel disease

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Abstract

Objective and design

To examine the effect of 3-[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM-G), a novel anti-inflammatory agent that inhibits lipopolysaccharide (LPS) activation of RAW264.7 macrophages, on murine models of colitis and RAW264.7 cells.

Materials and methods

Colitis was induced by rectally infusing trinitrobenzenesulfonic acid (TNBS) (1.5 mg in 50 % ethanol) in BALB/c mice or orally administering 3 % dextran sulfate sodium (DSS) for 5 days in C57BL/6 mice. The severity of colitis was assessed after intraperitoneally injecting DTCM-G (40 mg/kg). The anti-inflammatory properties of DTCM-G and its mechanisms were investigated in LPS-stimulated RAW264.7 cells.

Results

DTCM-G significantly ameliorated TNBS-induced colitis, according to the body weight loss, disease activity index, colonic obstruction, macroscopic colonic inflammation score, mucosal myeloperoxidase activity, and histopathology. Immunohistochemistry and isolated lamina propria mononuclear cells showed significantly reduced colonic F4/80+ and CD11b+ macrophage infiltration. DTCM-G significantly suppressed tumor necrosis factor (TNF)-α and interleukin (IL)-6 messenger RNA expression in the colon and attenuated DSS-induced colitis, according to the disease activity index and histopathology. In RAW264.7 cells, DTCM-G suppressed LPS-induced TNF-α/IL-6 production and enhanced glycogen synthase kinase-3β phosphorylation.

Conclusions

DTCM-G attenuated murine experimental colitis by inhibiting macrophage infiltration and inflammatory cytokine expression. Thus, DTCM-G may be a promising treatment for inflammatory bowel disease.

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Acknowledgments

This study was supported in part by funding from the Promotion of Fundamental Studies in Health Sciences initiative of the National Institute of Biomedical Innovation and a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science.

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Author notes

    Authors and Affiliations

    1. Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-ku, Sapporo, 060-8638, Japan

      Nobuki Ichikawa, Tohru Funakoshi, Masaomi Ogura, Nozomi Kobayashi, Masaaki Zaitsu, Tadashi Yoshida, Susumu Shibasaki, Yasuyuki Koshizuka, Yusuke Tsunetoshi, Masanori Sato, Takahiro Einama, Tomomi Suzuki & Satoru Todo

    2. Department of Transplant Surgery, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-ku, Sapporo, 060-8638, Japan

      Kenichiro Yamashita, Moto Fukai & Satoru Todo

    3. Department of Surgical Pathology, Sapporo-Kosei General Hospital, N-3, E-8-5, Chuo-ku, Sapporo, 060-0033, Japan

      Shin Ichihara

    4. Department of Molecular Target Medicine, Aichi Medical University, Yazakokarimata 1-1, Nagakute, 480-1195, Japan

      Kazuo Umezawa

    5. Faculty of Health Sciences, School of Medicine, Hokkaido University, N-12, W-5, Kita-ku, Sapporo, 060-0812, Japan

      Michitaka Ozaki

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    1. Nobuki Ichikawa
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    Correspondence to Kenichiro Yamashita or Satoru Todo.

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    Compliance with ethical standards

    All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All the procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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    The authors declare no conflicts of interest.

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    Responsible Editor: Yoshiya Tanaka.

    Kenichiro Yamashita and Satoru Todo have contributed equally as senior authors.

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    Ichikawa, N., Yamashita, K., Funakoshi, T. et al. Novel anti-inflammatory agent 3-[(dodecylthiocarbonyl)-methyl]-glutarimide ameliorates murine models of inflammatory bowel disease. Inflamm. Res. 65, 245–260 (2016). https://doi.org/10.1007/s00011-015-0911-0

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    • DOI: https://doi.org/10.1007/s00011-015-0911-0

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