BTZO-2, an antioxidant response element-activator, provides protection against lethal endotoxic shock in mice

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.