title: BTZO-15, an ARE-activator, ameliorates DSS- and TNBS-induced colitis in rats.
abstract: Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders that are primarily represented by ulcerative colitis and Crohn's disease. The etiology of IBD is not well understood; however, oxidative stress is considered a potential etiological and/or triggering factor for IBD. We have recently reported the identification of BTZO-1, an activator of antioxidant response element (ARE)-mediated gene expression, which protects cardiomyocytes from oxidative stress-induced insults. Here we describe the potential of BTZO-15, an active BTZO-1 derivative for ARE-activation with a favorable ADME-Tox profile, for the treatment of IBD. BTZO-15 induced expression of heme oxygenase-1 (HO-1), an ARE-regulated cytoprotective protein, and inhibited NO-induced cell death in IEC-18 cells. Large intestine shortening, rectum weight gain, diarrhea, intestinal bleeding, and an increase in rectal myeloperoxidase (MPO) activity were observed in a dextran sulfate sodium (DSS)-induced colitis rat model. Oral administration of BTZO-15 induced HO-1 expression in the rectum and attenuated DSS-induced changes. Furthermore BTZO-15 reduced the ulcerated area and rectal MPO activity in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rats without affecting rectal TNF-α levels. These results suggest that BTZO-15 is a promising compound for a novel IBD therapeutic drug with ARE activation properties.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yukitake
authors.forename: Haruhide
authors.initials: H
authors.lastname: Kimura
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Tajima
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Sato
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Imaeda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kajino
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takizawa
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016264:Dextran Sulfate; D005786:Gene Expression Regulation / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012007:Rectum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020218:Response Elements / Q000235:genetics*; D013843:Thiazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D014158:Transcription, Genetic / Q000187:drug effects; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D000975:Antioxidants; C568600:BTZO-15 compound; D008263:Macrophage Migration-Inhibitory Factors; D011725:Pyridines; D012333:RNA, Messenger; D013843:Thiazines; D009569:Nitric Oxide; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D051547:Heme Oxygenase-1; D005982:Glutathione Transferase; D019746:Intramolecular Oxidoreductases; C515599:Mif protein, rat