BTZO-15, an ARE-activator, ameliorates DSS- and TNBS-induced colitis in rats

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. W...

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Bibliographic Details
Published in:PloS one 2011-08, Vol.6 (8), p.e23256
Main Authors: Yukitake, Hiroshi, Kimura, Haruhide, Suzuki, Hirobumi, Tajima, Yasukazu, Sato, Yoshimi, Imaeda, Toshihiro, Kajino, Masahiro, Takizawa, Masayuki
Format: Article
Language:English
Subjects:
Activation
Animals
Antioxidants
Antioxidants - metabolism
Biology
Biosensors
Bleeding
Cardiomyocytes
Cell death
Cell Death - drug effects
Colitis - chemically induced
Colitis - drug therapy
Colitis - genetics
Colitis - pathology
Colon
Crohn's Disease
Cytokines
Dextran
Dextran Sulfate
Diarrhea
Enzymes
Etiology
Gastroenterology
Gene expression
Gene Expression Regulation - drug effects
Glutathione Transferase - genetics
Glutathione Transferase - metabolism
Heme
Heme oxygenase (decyclizing)
Heme Oxygenase-1 - genetics
Heme Oxygenase-1 - metabolism
Humans
Inflammatory bowel disease
Inflammatory bowel diseases
Intramolecular Oxidoreductases - metabolism
Large intestine
Macrophage Migration-Inhibitory Factors - metabolism
Medicine
Nitric Oxide - pharmacology
Oral administration
Oxidative stress
Oxygenase
Peroxidase
Pharmaceutical industry
Physics
Protein Binding - drug effects
Proteins
Pyridines - chemistry
Pyridines - metabolism
Pyridines - pharmacology
Pyridines - therapeutic use
Rats
Rectum
Rectum - drug effects
Rectum - metabolism
Rectum - pathology
Response Elements - genetics
RNA, Messenger - genetics
RNA, Messenger - metabolism
Rodents
Sensors
Sodium
Sulfate
Sulfonic acid
Thiazines - chemistry
Thiazines - metabolism
Thiazines - pharmacology
Thiazines - therapeutic use
Transcription, Genetic - drug effects
Trinitrobenzenesulfonic Acid
Tumor necrosis factor-α
Ulcerative colitis
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0023256