Premium
THE NOVEL SELECTIVE TOLL‐LIKE RECEPTOR 4 SIGNAL TRANSDUCTION INHIBITOR TAK‐242 PREVENTS ENDOTOXAEMIA IN CONSCIOUS GUINEA‐PIGS
Author(s) -
Kuno Masamune,
Nemoto Kayo,
Ninomiya Norifumi,
Inagaki Eiji,
Kubota Minoru,
Matsumoto Tatsumi,
Yokota Hiroyuki
Publication year - 2009
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2008.05121.x
Subject(s) - signal transduction , pharmacology , receptor , toll like receptor , guinea pig , chemistry , medicine , microbiology and biotechnology , biology , innate immune system
SUMMARY1 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.