The novel selective toll-like receptor 4 signal transduction inhibitor tak-242 prevents endotoxaemia in conscious Guinea-pigs.

Abstract

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.

• Authors: Masamune Kuno, Kayo Nemoto, Norifumi Ninomiya, Eiji Inagaki, Minoru Kubota, Tatsumi Matsumoto, Hiroyuki Yokota
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 36 Issue 5-6 Pg. 589-93 (May 2009) ISSN: 1440-1681 [Electronic] Australia
• PMID: 19673945 (Publication Type: Journal Article)

Chemical References

• Anti-Infective Agents
• Lipopolysaccharides
• Sulfonamides
• Toll-Like Receptor 4
• ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate

Topics

• Animals
• Anti-Infective Agents (therapeutic use)
• Blood Pressure (drug effects)
• Consciousness (physiology)
• Drug Evaluation, Preclinical
• Endotoxemia (chemically induced, mortality, physiopathology, prevention & control)
• Guinea Pigs
• Lipopolysaccharides (adverse effects)
• Male
• Models, Biological
• Muscle Tonus (drug effects)
• Muscle, Smooth (drug effects, physiology)
• Signal Transduction (drug effects)
• Substrate Specificity (drug effects)
• Sulfonamides (therapeutic use)
• Survival Analysis
• Toll-Like Receptor 4 (antagonists & inhibitors)