The novel selective toll-like receptor 4 signal transduction inhibitor tak-242 prevents endotoxaemia in conscious Guinea-pigs.
1. TAK-242 is a novel compound that suppresses nitric oxide and cytokine production by selectively inhibiting intracellular signals from toll-like receptor (TLR)-4. In the present study, we investigated the effectiveness of TAK-242 against sepsis using an endotoxaemia model in conscious and unrestricted guinea-pigs. Measures examined included muscle tension paralysis of the intestine, blood pressure, high morbidity group box (HMGB)-1 levels and survival rate. 2. Tension of the longitudinal muscle of the colon was monitored continuously by telemetry. Arterial blood pressure was monitored via a carotid artery catheter. TAK-242 was administered intravenously through a jugular vein catheter. Guinea-pigs were divided into a control group, given vehicle (placebo emulsion), and the experimental group, administered 3 or 10 mg/kg TAK-242, 1 h before administration of 10 mg/kg lipopolysaccharide (LPS). 3. In the control group, the tension of the longitudinal muscle of the colon decreased in a time-dependent manner and blood pressure was reduced, with maximal effects observed 1-3 h after administration of LPS. In the TAK-242-treated group, LPS-induced relaxation of the intestine and hypotension were significantly inhibited. In the control group, HMGB-1 levels were increased after LPS administration and this reaction was significantly blocked in the TAK-242-treated group. Importantly, survival rate was increased after TAK-242 treatment. 4. In conlusion, the results of the present study show that TAK-242 inhibited the symptoms associated with endotoxaemia in a guinea-pig model of sepsis and that it may, therefore, be an effective treatment for sepsis.
Kuno
Masamune
M
Department of Emergency and Critical Care Medicine, Nippon Medical School, Tokyo, Japan. jean@nms.ac.jp
Nemoto
Kayo
K
Ninomiya
Norifumi
N
Inagaki
Eiji
E
Kubota
Minoru
M
Matsumoto
Tatsumi
T
Yokota
Hiroyuki
H
D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D003243:Consciousness / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D019446:Endotoxemia / Q000139:chemically induced / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D006168:Guinea Pigs; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D008954:Models, Biological; D009129:Muscle Tonus / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects; D013449:Sulfonamides / Q000627:therapeutic use*; D016019:Survival Analysis; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*
D000890:Anti-Infective Agents; D008070:Lipopolysaccharides; D013449:Sulfonamides; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate