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

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.

• Authors: Ling Li, Manuel Salto-Tellez, Choon-Hong Tan, Matthew Whiteman, Philip K Moore
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 47 Issue 1 Pg. 103-13 (Jul 01 2009) ISSN: 1873-4596 [Electronic] United States
• PMID: 19375498 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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