Effects of the anti-sepsis drug, (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD-712), on mortality, inflammation, and organ injuries in rodent sepsis models

Arch Pharm Res. 2011 Mar;34(3):485-94. doi: 10.1007/s12272-011-0318-6. Epub 2011 May 6.

Abstract

CKD-712 is a 1-naphthyl analog of higenamine that has been reported to have potent antiinflammatory and thus anti-sepsis effects. The purpose of this study was to investigate the potential of CKD-712 as a medicine for sepsis and to confirm its protective effects on organs in animal sepsis models. Pretreatment with CKD-712 dose-dependently increased survival rate in a lipopolysaccharide-induced sepsis model in mice. Body temperature decrease, an important pre-symptom of septic death, was also prevented by CKD-712. CKD-712 still significantly increased survival rate even when administered one and four hours after lipopolysaccharide injection. Therapeutic efficacy of CKD-712 was also confirmed against sepsis following zymosan-induced endotoxemia and in cecal ligation and puncture surgery in mice. In a disseminated intravascular coagulation model in rats, CKD-712 showed organ-protective effect by reducing serum glutamate-oxaloacetate transaminase, glutamate-pyruvate transferase, blood urea nitrogen, and creatinine levels. CKD-712 also prevented histological damage to the lung and liver. In this same model, CKD-712 showed anti-inflammatory effects through decreases in tumor necrosis factor-α and interleukin-6 in the blood and reduced translocation of nuclear factor-κB to the nuclei of lung cells. CKD-712 administration also diminished infiltration of leukocytes into the lung and liver. Taken together, these results show that CKD-712 has excellent potential as an effective medicine for sepsis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Cytokines / blood
  • Cytokines / immunology*
  • Disease Models, Animal
  • Disseminated Intravascular Coagulation / drug therapy*
  • Disseminated Intravascular Coagulation / immunology
  • Disseminated Intravascular Coagulation / pathology
  • Endotoxemia / drug therapy
  • Endotoxemia / immunology
  • Endotoxemia / pathology
  • Fever / drug therapy
  • Fever / immunology
  • Fever / pathology
  • Kidney / drug effects
  • Kidney / pathology
  • Lipopolysaccharides / pharmacology
  • Liver / drug effects
  • Liver / pathology
  • Lung / drug effects
  • Lung / pathology
  • Male
  • Mice
  • Mice, Inbred ICR
  • Rats
  • Rats, Sprague-Dawley
  • Sepsis / drug therapy*
  • Sepsis / immunology
  • Sepsis / pathology
  • Survival Analysis
  • Tetrahydroisoquinolines / administration & dosage
  • Tetrahydroisoquinolines / therapeutic use*
  • Zymosan / pharmacology

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • Lipopolysaccharides
  • Tetrahydroisoquinolines
  • YS 49
  • Zymosan