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Benzisothiazole derivative inhibits toll-like receptor 4 signal transduction and prevents mice from the lethal shock
Critical Care volume 8, Article number: P202 (2004)
Sepsis is a syndrome, a consequence of an overwhelming systemic response to infection. It rapidly leads to organ dysfunction, which accompanies systemic inflammation and hematological abnormalities. In Gram-negative bacteria, lipopolysaccharide (LPS) has a dominant role for the activation of various cells, which secrete several proinflammatory cytokines including TNF-α. These cytokines are also important in inducing a procoagulant effect in sepsis. On the other hand, toll-like receptor 4 (TLR4) is responsible for the LPS signaling and causes the activation of NF-κB. It is clear that an inappropriate TLR response to bacterial infection could have critical consequences. Therefore, TLR4 signal inhibitor is attractive as a therapeutic medication for sepsis.
The benzisothiazole derivative (M62812) was found as a TLR4 signal transduction inhibitor using the reporter gene assay system. It also suppressed LPS-induced upregulation of proinflammatory cytokines, adhesion molecules and procoagulant activity in human vascular endothelial cells and/or peripheral mononuclear cells. The half-maximal inhibitory concentrations (IC50) of this compound in these assays were ranging from 1 to 3 μg/ml. Single intravenous administration of M62812 (10 mg/kg) protected mice from death in murine D-galactosamine-sensitized endotoxin shock model (Table 1). In this model, M62812 (20 mg/kg) completely improved the elevation of inflammatory cytokines and the hematological abnormalities. Furthermore, M62812 (20 mg/kg) also prevented mice from the lethal shock in murine cecal ligation and puncture model.
LPS is a potent and predominant microbial mediator that induces an intense inflammation and procoagulant response, which are closely correlated events. M62812 inhibits those responses in vitro and prevents lethal shock in animal models. Therefore, we concluded that it will become a novel therapeutic medication for sepsis and septic shock by inhibiting TLR4 signal transduction and improving endothelial cell and leukocyte cell functions.
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Hosaka, Y., Shimizu, Y., Nakamura, M. et al. Benzisothiazole derivative inhibits toll-like receptor 4 signal transduction and prevents mice from the lethal shock. Crit Care 8 (Suppl 1), P202 (2004). https://doi.org/10.1186/cc2669