| Abstract | S-diclofenac (2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(3H-1,2,dithiol-3-thione-5-yl)phenyl ester; ACS 15) is a novel molecule comprising a hydrogen sulfide (H2S)-releasing dithiol-thione moiety attached by an ester linkage to diclofenac. S-diclofenac administration inhibited lipopolysaccharide-induced inflammation (as evidenced by reduced lung and liver myeloperoxidase activity) and caused significantly less gastric toxicity than diclofenac. S-diclofenac did not affect blood pressure or heart rate of the anesthetized rat. S-diclofenac administration downregulated expression of genes encoding enzymes which synthesize nitric oxide, prostanoids, and H2S; reduced plasma IL-1beta/TNF-alpha; and elevated plasma IL-10. Reduced liver NF-kappaB p65 and AP-1/c-fos DNA-binding activity was also observed. These effects were mimicked in large part by a combination of diclofenac plus an H2S-releasing moiety (ADT-OH). Incubation of S-diclofenac (100 microM) with rat plasma or liver homogenate caused a time-dependent release of H2S, which was inhibited by sodium fluoride (10 mM). Administration of S-diclofenac (47.2 micromol/kg, i.p.) to conscious rats significantly increased plasma H2S concentration (at 45 min and 6 h). We propose that H2S release from S-diclofenac in vivo contributes to the observed effects. |
| Authors | Ling Li, Giuseppe Rossoni, Anna Sparatore, Lin Chiou Lee, Piero Del Soldato, Philip Keith Moore
(Affiliation: Cardiovascular Biology Research Group, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 18 Medical Drive, Singapore 117597.)
|
| Journal | Free radical biology & medicine
(Free Radic Biol Med)
Vol. 42
Issue 5
Pg. 706-19
(Mar 1 2007)
ISSN: 0891-5849 United States |
| PMID | 17291994
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- 2-((2,6-dichlorophenyl)amino)benzeneacetic acid 4-(3H-1,2-dithiol-3-thione-5-yl)phenyl ester
- Anti-Inflammatory Agents
- Lipopolysaccharides
- Thiones
- Diclofenac
|
| Topics |
- Animals
- Anti-Inflammatory Agents
(adverse effects, pharmacokinetics, pharmacology, therapeutic use)
- Blood Pressure
(drug effects)
- Diclofenac
(adverse effects, analogs & derivatives, pharmacokinetics, pharmacology, therapeutic use)
- Drug Evaluation, Preclinical
- Gastrointestinal Tract
(drug effects)
- Lipopolysaccharides
- Male
- Models, Biological
- Rats
- Rats, Sprague-Dawley
- Shock, Septic
(chemically induced, prevention & control)
- Thiones
(pharmacology)
|
