Toll-like receptor 4 signal transduction inhibitor, M62812, suppresses endothelial cell and leukocyte activation and prevents lethal septic shock in mice.
Sepsis occurs when microbes activate toll-like receptors (TLRs) stimulating widespread inflammation and activating coagulation cascades. TLR4 signal transduction has been recognized as a key pathway for lipopolysaccharide (LPS)-induced activation of various cells and an attractive target for treatment of sepsis. We found a new benzisothiazole derivative, M62812 that inhibits TLR4 signal transduction. This compound suppressed LPS-induced upregulation of inflammatory cytokines, adhesion molecules and procoagulant activity in human vascular endothelial cells and peripheral mononuclear cells. The half maximal inhibitory concentrations in these assays ranged from 1 to 3 microg/ml. Single intravenous administration of M62812 (10-20 mg/kg) protected mice from lethality and reduced inflammatory and coagulatory parameters in a murine d-galactosamine-sensitized endotoxin shock model. M62812 (20 mg/kg) also prevented mice from lethality in a murine cecal ligation and puncture model. These results suggest that inhibition of TLR4 signal transduction can suppress coagulation as well as inflammation during sepsis and may be clinically beneficial in sepsis treatment.
Nakamura
Masaki
M
Discovery Research, Mochida Pharmaceutical Co., LTD., Shizuoka 412-8524, Japan. mnakamur@mochida.co.jp
Shimizu
Yusuke
Y
Sato
Yasuko
Y
Miyazaki
Yutaka
Y
Satoh
Tsutomu
T
Mizuno
Masashi
M
Kato
Yutaka
Y
Hosaka
Yoshitaka
Y
Furusako
Shoji
S
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004731:Endotoxins; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007275:Injections, Intravenous; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012772:Shock, Septic / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D014471:Umbilical Veins; D015854:Up-Regulation
D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D004731:Endotoxins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C525083:M62812; D013844:Thiazoles; D051197:Toll-Like Receptor 4