NCX 2057, a novel NO-releasing derivative of ferulic acid, suppresses inflammatory and nociceptive responses inin vitroandin vivomodels


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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 (ID50= 100 μmol·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 μmol·kg−1]. NCX 2057 reversed carrageenan-induced hyperalgesic responses in mice and inhibited prostaglandin E2 formation in paw exudates. Finally, NCX 2057 competitively inhibited COX-1 and COX-2 activities in whole RAW macophages (IC50= 14.7 ± 7.4 and 21.6 ± 7.5 μM, 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.

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