title: BTZO-2, an antioxidant response element-activator, provides protection against lethal endotoxic shock in mice.
abstract: We recently reported a unique antioxidant response element (ARE)-activator, BTZO-1, which induced expression of cytoprotective proteins such as heme oxygenase-1 (HO-1) and suppressed oxidative stress-induced cardiomyocyte apoptosis via binding to macrophage migration inhibitory factor (MIF). HO-1 induction and apoptosis inhibition have been reported to improve the outcomes following experimental sepsis by protecting the organs. Therefore, we investigated the potential of BTZO-2, an active BTZO-1 derivative, as a drug for sepsis. BTZO-2 significantly protected mice from the endotoxic shock induced by 5mg/kg lipopolysaccharide (LPS); survival rates increased from 42% to 100%. In contrast, BTZO-2 did not provide significant protection to mice from the shock induced by 10 μg/kg LPS together with d-galactosamine (d-GalN, hepatocyte-specific transcription inhibitor) (LPS/d-GalN). Hepatic HO-1 protein was up-regulated by BTZO-2 in mice injected with 5mg/kg LPS, but not in those injected with 10 μg/kg LPS/d-GalN. Interestingly, BTZO-2 showed little or no effect on LPS-induced up-regulation of plasma cytokine levels in mice. Thus, the organ protection mediated by HO-1 may have a pivotal role in the pharmacological effect of BTZO-2. These results suggest that BTZO-2 is a promising compound for a novel drug for sepsis.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yukitake
authors.forename: Haruhide
authors.initials: H
authors.lastname: Kimura
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Tajima
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Sato
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kajino
authors.forename: Seiichi
authors.initials: S
authors.lastname: Tanida
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takizawa
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D051547:Heme Oxygenase-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D020218:Response Elements / Q000187:drug effects*; D012772:Shock, Septic / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D013843:Thiazines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C557081:2-pyridin-2-yl-4H-1,3-benzothiazin-4-one; C582660:3-(6-(4-oxo-4H-1,3-benzothiazin-2-yl)pyridin-2-yl)propanoic acid; D000975:Antioxidants; D016207:Cytokines; D008070:Lipopolysaccharides; D011725:Pyridines; D013843:Thiazines; D051547:Heme Oxygenase-1