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

Nobuki Ichikawa, Kenichiro Yamashita, Tohru Funakoshi, Shin Ichihara, Moto Fukai, Masaomi Ogura, Nozomi Kobayashi, Masaaki Zaitsu, Tadashi Yoshida, Susumu Shibasaki, Yasuyuki Koshizuka, Yusuke Tsunetoshi, Masanori Sato, Takahiro Einama, Michitaka Ozaki, Kazuo Umezawa, Tomomi Suzuki, Satoru Todo

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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.

Original languageEnglish
Pages (from-to)245-260
Number of pages16
JournalInflammation Research
Volume65
Issue number3
DOIs
Publication statusPublished - 01-03-2016

All Science Journal Classification (ASJC) codes

  • Immunology
  • Pharmacology

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    Ichikawa, N., Yamashita, K., Funakoshi, T., Ichihara, S., Fukai, M., Ogura, M., Kobayashi, N., Zaitsu, M., Yoshida, T., Shibasaki, S., Koshizuka, Y., Tsunetoshi, Y., Sato, M., Einama, T., Ozaki, M., Umezawa, K., Suzuki, T., & Todo, S. (2016). Novel anti-inflammatory agent 3-[(dodecylthiocarbonyl)-methyl]-glutarimide ameliorates murine models of inflammatory bowel disease. Inflammation Research, 65(3), 245-260. https://doi.org/10.1007/s00011-015-0911-0