GYY4137, a novel hydrogen sulfide-releasing molecule, protects against endotoxic shock in the rat

Free Radic Biol Med. 2009 Jul 1;47(1):103-13. doi: 10.1016/j.freeradbiomed.2009.04.014. Epub 2009 Apr 15.

Abstract

GYY4137 (morpholin-4-ium-4-methoxyphenyl(morpholino) phosphinodithioate) is a slow-releasing hydrogen sulfide (H(2)S) donor. Administration of GYY4137 (50 mg/kg, iv) to anesthetized rats 10 min after lipopolysaccharide (LPS; 4 mg/kg, iv) decreased the slowly developing hypotension. GYY4137 inhibited LPS-induced TNF-alpha production in rat blood and reduced the LPS-evoked rise in NF-kappaB activation, inducible nitric oxide synthase/cyclooxygenase-2 expression, and generation of PGE(2) and nitrate/nitrite in RAW 264.7 macrophages. GYY4137 (50 mg/kg, ip) administered to conscious rats 1 or 2 h after (but not 1 h before) LPS decreased the subsequent (4 h) rise in plasma proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6), nitrite/nitrate, C-reactive protein, and L-selectin. GYY4137 administration also decreased the LPS-evoked increase in lung myeloperoxidase activity, increased plasma concentration of the anti-inflammatory cytokine IL-10, and decreased tissue damage as determined histologically and by measurement of plasma creatinine and alanine aminotransferase activity. Time-expired GYY4137 (50 mg/kg, ip) did not affect the LPS-induced rise in plasma TNF-alpha or lung myeloperoxidase activity. GYY4137 also decreased the LPS-mediated upregulation of liver transcription factors (NF-kappaB and STAT-3). These results suggest an anti-inflammatory effect of GYY4137. The possibility that GYY4137 and other slow-releasing H(2)S donors exert anti-inflammatory activity in other models of inflammation and in humans warrants further study.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / administration & dosage*
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / immunology
  • Anti-Inflammatory Agents / pharmacology
  • Blood Pressure / drug effects
  • Cell Line
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / immunology
  • Cyclooxygenase 2 / metabolism
  • Cytokines / genetics
  • Cytokines / immunology
  • Cytokines / metabolism
  • Cytoprotection / drug effects
  • Hydrogen Sulfide / chemistry
  • Hydrogen Sulfide / metabolism*
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Lung / drug effects
  • Lung / enzymology
  • Lung / pathology
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice
  • Morpholines / administration & dosage*
  • Morpholines / chemistry
  • Morpholines / immunology
  • Morpholines / pharmacology
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Organothiophosphorus Compounds / administration & dosage*
  • Organothiophosphorus Compounds / chemistry
  • Organothiophosphorus Compounds / immunology
  • Organothiophosphorus Compounds / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Shock, Septic / chemically induced
  • Shock, Septic / immunology
  • Shock, Septic / pathology
  • Shock, Septic / prevention & control*

Substances

  • Anti-Inflammatory Agents
  • Cytokines
  • GYY 4137
  • Lipopolysaccharides
  • Morpholines
  • NF-kappa B
  • Organothiophosphorus Compounds
  • STAT3 Transcription Factor
  • Stat3 protein, rat
  • Cyclooxygenase 2
  • Hydrogen Sulfide