6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) from Wasabia japonica alleviates inflammatory bowel disease (IBD) by potential inhibition of glycogen synthase kinase 3 beta (GSK-3β)

• Published in: European journal of medicinal chemistry Vol. 216; p. 113250
• Main Authors: Lohning, Anna, Kidachi, Yumi, Kamiie, Katsuyoshi, Sasaki, Kazuo, Ryoyama, Kazuo, Yamaguchi, Hideaki
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15-04-2021
• Subjects: 6-MITC; Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - metabolism; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Cell Line; Crohn’s disease (CD); Dextran Sulfate - toxicity; Down-Regulation - drug effects; Female; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - metabolism; GSK-3β inhibitor; Humans; Inflammatory bowel disease (IBD); Inflammatory Bowel Diseases - chemically induced; Inflammatory Bowel Diseases - drug therapy; Inflammatory Bowel Diseases - pathology; Interleukin-6 - metabolism; Isothiocyanates - chemistry; Isothiocyanates - metabolism; Isothiocyanates - pharmacology; Isothiocyanates - therapeutic use; Lipopolysaccharides - pharmacology; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Inbred BALB C; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-κB regulation; Nitric Oxide Synthase Type II - metabolism; Signal Transduction - drug effects; Ulcerative colitis (UC); Up-Regulation - drug effects; Wasabia - chemistry; Wasabia - metabolism; GSK-3β inhibitor; NF-κB regulation; 6-MITC; Inflammatory bowel disease (IBD); Crohn’s disease (CD); Ulcerative colitis (UC)
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113250

Inflammatory bowel disease (IBD) describes a set of disorders involving alterations to gastrointestinal physiology and mucosal immunity. Unravelling its complex pathophysiology is important since many IBD patients are refractory to or suffer adverse side effects from current treatments. Isothiocyanates (ITCs), such as 6-(methylsulfinyl)hexyl ITC (6-MITC) in Wasabia japonica, have potential anti-inflammatory activity. We aimed to elucidate the pathways through which 6-MITC alleviates inflammation by examining its role in the nuclear factor-kappa B (NF-κB) pathway through inhibition of glycogen synthase kinase 3 beta (GSK-3β) using a chemically induced murine model of IBD, cell-based and in silico techniques. The effects of 6-MITC and two NF-κB inhibitors, sulfasalazine (SS), pyrrolidine dithiolcarbamate (PDTC) were investigated on a dextran sulfate sodium (DSS)-induced murine mouse model of acute and chronic colitis using macroscopic measurements and pro-inflammatory markers. The effect of 6-MITC on NF-κB induction was assessed using a murine macrophage cell line. Complexes of GSK-3β-6-MITC and GSK-3β-ATP were generated in silico to elucidate the mechanism of 6-MITC’s direct inhibition of GSK-3β. Changes in pro-inflammatory markers, inducible nitric oxide synthase (iNOS) (increased) and interleukin-6 (IL-6) (decreased) demonstrated that iNOS regulation occurred at the translational level. Intraperitoneal (ip) injection of 6-MITC to the colitis-induced mice ameliorated weight loss whereas oral administration had negligible effect. Fecal blood and colon weight/length ratio parameters improved on treatment with 6-MITC and the other NF-κB inhibitors. Levels of NF-κB decreased upon addition of 6-MITC in vitro while structural studies showed 6-MITC acts competitively to inhibit GSK-3β at the ATP binding site.
In this study we demonstrated that 6-MITC inhibits NF-κB signaling via GSK-3β inhibition ameliorating fecal blood, colonic alterations and DSS-induced weight loss indirectly indicating reduced intestinal stress. Taken together these results suggest a role for 6-MITC in the treatment of IBD acting to alleviate inflammation through the GSK-3β/NF-κB pathway. Furthermore, the GSK-3β-6-MITC model can be utilized as a basis for development of novel therapeutics targeting GSK-3β for use in other disorders including cancer.
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•6-MITC from wasabi has potential anti-inflammatory activity for the alleviation of inflammatory bowel disease.•In a DSS-induced, murine model of colitis, 6-MITC ameliorated symptoms of weight loss, fecal blood as well as improving colon weight/length ratio.•6-MITC acts by interfering with NF-κB signaling via competitive inhibition of GSK-3β.•The GSK-3β-6-MITC model generated can be used for development of drugs targeting other disorders including cancer.