Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute inflammation.

Abstract

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. The PPAR-gamma receptor subtype appears to play a pivotal role in the regulation of cellular proliferation and inflammation. The thiazolidinedione rosiglitazone (Avandia) is a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, that was recently approved by the Food and Drug Administration for treatment of type II diabetes mellitus. In the present study, we have investigated the effects of rosiglitazone in animal models of acute inflammation (carrageenan-induced paw oedema and carrageenan-induced pleurisy). We report here for the first time that rosiglitazone (given at 1, 3 or 10 mg/kg i.p. concomitantly with carrageenan injection in the paw oedema model, or at 3, 10 or 30 mg/kg i.p. 15 min before carrageenan administration in the pleurisy model) exerts potent anti-inflammatory effects (e.g. inhibition of paw oedema, pleural exudate formation, mononuclear cell infiltration and histological injury) in vivo. Furthermore, rosiglitazone reduced: (1) the increase in the staining (immunohistochemistry) for nitrotyrosine and poly (ADP-ribose) polymerase (PARP), (2) the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), intercellular adhesion molecules-1 (ICAM-1) and P-selectin in the lungs of carrageenan-treated rats. In order to elucidate whether the protective effect of rosiglitazone is related to activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, bisphenol A diglycidyl ether (BADGE), on the protective effects of rosiglitazone. BADGE (30 mg/kg i.p.) administered 30 min prior to treatment with rosiglitazone significantly antagonized the effect of the PPAR-gamma agonist and thus abolished the anti-inflammatory effects of rosiglitazone. We propose that rosiglitazone and other potent PPAR-gamma agonists may be useful in the therapy of inflammation.

• Authors: Salvatore Cuzzocrea, Barbara Pisano, Laura Dugo, Angela Ianaro, Pasquale Maffia, Nimesh S A Patel, Rosanna Di Paola, Armando Ialenti, Tiziana Genovese, Prabal K Chatterjee, Massimo Di Rosa, Achille P Caputi, Christoph Thiemermann
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 483 Issue 1 Pg. 79-93 (Jan 01 2004) ISSN: 0014-2999 [Print] Netherlands
• PMID: 14709329 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• Isoenzymes
• Nitrates
• Nitrites
• Receptors, Cytoplasmic and Nuclear
• Thiazolidinediones
• Transcription Factors
• Rosiglitazone
• Tyrosine
• Carrageenan
• Peroxidase
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nos2 protein, rat
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases
• Poly(ADP-ribose) Polymerases
• Dinoprostone

Topics

• Animals
• Anti-Inflammatory Agents
• Carrageenan
• Cyclooxygenase 2
• Cytokines (biosynthesis)
• Dinoprostone (metabolism)
• Edema (chemically induced, pathology, prevention & control)
• Exudates and Transudates (metabolism)
• Immunohistochemistry
• Isoenzymes (biosynthesis)
• Lipid Peroxidation (drug effects)
• Lung (pathology)
• Male
• Neutrophil Infiltration (drug effects)
• Nitrates (metabolism)
• Nitric Oxide Synthase (biosynthesis)
• Nitric Oxide Synthase Type II
• Nitrites (metabolism)
• Peroxidase (metabolism)
• Pleurisy (chemically induced, pathology, prevention & control)
• Poly(ADP-ribose) Polymerases (metabolism)
• Prostaglandin-Endoperoxide Synthases (biosynthesis)
• Rats
• Rats, Sprague-Dawley
• Receptors, Cytoplasmic and Nuclear (agonists, antagonists & inhibitors)
• Rosiglitazone
• Thiazolidinediones (antagonists & inhibitors, pharmacology)
• Transcription Factors (agonists, antagonists & inhibitors)
• Tyrosine (metabolism)