Anti-inflammatory synergy of MEN16132, a kinin B(2) receptor antagonist, and dexamethasone in carrageenan-induced knee joint arthritis in rats.

Abstract

BACKGROUND AND PURPOSE:

Bradykinin, through its B(2) receptor, is involved in inflammatory processes related to arthropathies. In carrageenan and lipopolysaccharide (LPS)-induced arthritis in rat, the anti-inflammatory activity of MEN16132, a potent and selective kinin B(2) receptor antagonist, was compared with that of steroidal and nonsteroidal anti-inflammatory drugs. The interaction between MEN16132 and dexamethasone was also investigated.

EXPERIMENTAL APPROACH:

Drugs, alone or in combination, were injected into the knee joint 30min before intra-articular administration of carrageenan or LPS, in pentobarbital anaesthetized rats. Effects on incapacitation, oedema, neutrophil recruitment and kallikrein system activation, in the knee joint, were assessed.

KEY RESULTS:

MEN16132 and dexamethasone (10-300µg per knee) dose-dependently reduced carrageenan-induced joint pain, oedema and neutrophil infiltration, reaching a maximal inhibition of about 50%. Dexketoprofen exerted a similar analgesic activity, whereas it did not affect the other inflammatory responses. MEN16132 showed a partial inhibition of LPS-induced joint pain, whereas dexamethasone produced a full analgesic effect. Combination of MEN16132 and dexamethasone showed a strong synergistic interaction in inhibiting both carrageenan and LPS-induced knee joint inflammation. Dexamethasone did not prevent the contact activation of prekallikrein by carrageenan and the subsequent release of kallikreins and bradykinin in the synovium.

CONCLUSIONS AND IMPLICATIONS:

Steroids and kinin B(2) receptor antagonists appear to relieve arthritic symptoms induced by carrageenan or LPS and act synergistically to inhibit joint inflammation. This could have interesting therapeutic implications, possibly opening the way for combination therapies in the control of inflammatory arthropathies.

• Authors: C Valenti, S Giuliani, C Cialdai, M Tramontana, C A Maggi
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 161 Issue 7 Pg. 1616-27 (Dec 2010) ISSN: 1476-5381 [Electronic] England
• PMID: 20726984 (Publication Type: Journal Article)
• Copyright: © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.

Chemical References

• (4-amino-5-(4-(4-(2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido)tetrahydro-2H-4-pyranoylcarbonyl)piperazino)-5-oxopentyl)(trimethyl)ammonium
• Anti-Inflammatory Agents, Non-Steroidal
• Bradykinin B2 Receptor Antagonists
• Lipopolysaccharides
• Receptor, Bradykinin B2
• Sulfonamides
• Dexamethasone
• Carrageenan
• Ornithine
• Peroxidase
• Kallikreins
• Bradykinin

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Arthritis, Experimental (chemically induced, drug therapy, metabolism)
• Bradykinin (metabolism)
• Bradykinin B2 Receptor Antagonists
• Carrageenan
• Dexamethasone (pharmacology)
• Drug Synergism
• Injections, Intra-Articular
• Kallikreins (blood)
• Knee Joint
• Lipopolysaccharides
• Male
• Ornithine (analogs & derivatives, pharmacology)
• Peroxidase (metabolism)
• Rats
• Rats, Wistar
• Receptor, Bradykinin B2 (metabolism)
• Sulfonamides (pharmacology)