The ameliorative effects of a hypnotic bromvalerylurea in sepsis.
Sepsis is a severe pathologic event, frequently causing death in critically ill patients. However, there are no approved drugs to treat sepsis, despite clinical trials of many agents that have distinct targets. Therefore, a novel effective treatment should be developed based on the pathogenesis of sepsis. We recently observed that an old hypnotic drug, bromvalerylurea (BU) suppressed expression of many kinds of pro- and anti-inflammatory mediators in LPS- or interferon-γ activated alveolar and peritoneal macrophages (AMs and PMs). Taken the anti-inflammatory effects of BU on macrophages, we challenged it to septic rats that had been subjected to cecum-ligation and puncture (CLP). BU was subcutaneously administered to septic rats twice per day. Seven days after CLP treatment, 85% of septic rats administrated vehicle had died, whereas administration of BU reduce the rate to 50%. Septic rats showed symptoms of multi-organ failure; respiratory, circulatory and renal system failures as revealed by histopathological analyses, blood gas test and others. BU ameliorated these symptoms. BU also prevented elevated serum-IL-6 level as well as IL-6 mRNA expression in septic rats. Collectively, BU might be a novel agent to ameliorate sepsis by preventing the onset of MOF.
Department of Emergency Medicine, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan; Department of Gastrointestinal Surgery and Surgical Oncology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
Satoshi
S
Kikuchi
Department of Anesthesiology and Resuscitology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
Tasuku
T
Nishihara
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan; Department of Anesthesiology and Resuscitology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
Shun
S
Kawasaki
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan; Department of Anesthesiology and Resuscitology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
Naoki
N
Abe
Department of Gastrointestinal Surgery and Surgical Oncology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
Jun
J
Kuwabara
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
Mohammed E
ME
Choudhury
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
Hisaaki
H
Takahashi
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
Hajime
H
Yano
Department of Anesthesiology and Resuscitology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
Takumi
T
Nagaro
Department of Gastrointestinal Surgery and Surgical Oncology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
Yuji
Y
Watanabe
Department of Emergency Medicine, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
Mayuki
M
Aibiki
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan. Electronic address: jtanaka@m.ehime-u.ac.jp.
Junya
J
Tanaka
D000818:Animals; D001968:Bromisovalum / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006993:Hypnotics and Sedatives / Q000627:therapeutic use*; D020672:I-kappa B Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009102:Multiple Organ Failure / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050794:STAT1 Transcription Factor / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology
D016207:Cytokines; D006993:Hypnotics and Sedatives; D020672:I-kappa B Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D001968:Bromisovalum; D007371:Interferon-gamma
Inflammation; LPS; Macrophage; STAT transcription factor; TLR4