NCX 2057, a novel NO-releasing derivative of ferulic acid, suppresses inflammatory and nociceptive responses in in vitro and in vivo models.

Abstract

BACKGROUND AND PURPOSE:

We previously reported that NCX 2057, a compound comprising a nitric oxide (NO)-releasing moiety and the natural antioxidant, ferulic acid (FA), inhibits pro-inflammatory mediators through NO-mediated gene regulation. Here, we have assessed the activities of NCX 2057 in models of inflammatory and neuropathic pain, and characterized its effects on cyclooxygenase (COX)-1 and COX-2.

EXPERIMENTAL APPROACH:

Anti-nociceptive and anti-inflammatory activities of NCX 2057 were measured in vitro and in vivo in models of inflammatory (carrageenan) and neuropathic (chronic constriction injury; CCI) pain. Effects of NCX 2057 were measured on COX-1 and COX-2 activities in RAW 264.7 macrophages.

KEY RESULTS:

NCX 2057 dose-dependently inhibited single motor unit responses to noxious mechanical stimulation (ID(50)= 100 micromol kg(-1)) and wind-up responses in rats with paw inflammation induced by carrageenan. Moreover, NCX 2057 inhibited allodynic responses following CCI of the sciatic nerve [ipsilateral Paw Withdrawal Threshold (g): vehicle: 41.4 +/- 3.3; NCX 2057: 76.3 +/- 4.8 FA: 37.9 +/- 15.5 at 175 micromol kg(-1)]. NCX 2057 reversed carrageenan-induced hyperalgesic responses in mice and inhibited prostaglandin E(2) formation in paw exudates. Finally, NCX 2057 competitively inhibited COX-1 and COX-2 activities in whole RAW macophages (IC(50)= 14.7 +/- 7.4 and 21.6 +/- 7.5 microM, respectively). None of these properties were exhibited by equivalent treatments with FA or standard NO donor compounds.

CONCLUSIONS AND IMPLICATIONS:

These studies indicate that NCX 2057 is effective in chronic inflammatory and neuropathic pain models, probably because of its particular combination of anti-COX, antioxidant and NO-releasing properties.

• Authors: Daniela Ronchetti, Valentina Borghi, Gema Gaitan, Juan F Herrero, Francesco Impagnatiello
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 158 Issue 2 Pg. 569-79 (Sep 2009) ISSN: 1476-5381 [Electronic] England
• PMID: 19594750 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-((4-hydroxy-3-methoxyphenyl)-2-propenoic acid 4-nitrooxy)butyl ester
• Analgesics
• Anti-Inflammatory Agents
• Antioxidants
• Butanes
• Nitro Compounds
• Nitric Oxide
• Cyclooxygenase 1
• Cyclooxygenase 2

Topics

• Analgesics (administration & dosage, pharmacology)
• Animals
• Anti-Inflammatory Agents (administration & dosage, pharmacology)
• Antioxidants (administration & dosage, pharmacology)
• Butanes (administration & dosage, pharmacology)
• Cyclooxygenase 1 (drug effects, metabolism)
• Cyclooxygenase 2 (drug effects, metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Inflammation (drug therapy, physiopathology)
• Inhibitory Concentration 50
• Macrophages
• Male
• Mice
• Nitric Oxide (metabolism)
• Nitro Compounds (administration & dosage, pharmacology)
• Pain (drug therapy, physiopathology)
• Rats
• Rats, Wistar