BTZO-15, an ARE-activator, ameliorates DSS- and TNBS-induced colitis in rats |
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Authors: | Yukitake Hiroshi Kimura Haruhide Suzuki Hirobumi Tajima Yasukazu Sato Yoshimi Imaeda Toshihiro Kajino Masahiro Takizawa Masayuki |
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Affiliation: | 1Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan;2Chemistry, Manufacturing and Controls, Takeda Pharmaceutical Company Limited, Osaka, Japan;Charité-University Medicine Berlin, Germany |
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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. |
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