21‐NO‐prednisolone is a novel nitric oxide‐releasing derivative of prednisolone with enhanced anti‐inflammatory properties

Anti‐inflammatory effects of a novel derivative of the glucocorticoid prednisolone were investigated. NCX‐1015 (prednisolone 21‐[(4′‐nitrooxymethyl)benzoate]) incubation in human platelet‐rich plasma produced a time (0–60 min) and concentration (3–300 μ M ) dependent release of nitrite, that was mirrored by accumulation of cyclic guanosine monophosphate in the human platelets. Intraperitoneal injection of NCX‐1015 to mice (up to 27.7 μmol kg −1 ) produced nitrite accumulation in the peritoneal cavity maximal at 60 min. NCX‐1015 dose‐dependently induced the steroid sensitive cell surface marker CD163 in human peripheral blood mononuclear cells (PBMCs). NCX‐1015 was more potent than prednisolone in inducing CD163. Similarly, lipopolysaccharide induced interleukin‐1β release from these cells was inhibited by NCX‐1015 with higher potency than prednisolone. In the zymosan peritonitis model, NCX‐1015 was more active than prednisolone in suppressing neutrophil extravasation (ED 50 of 5.5 and 25.8 μmol kg −1 , respectively), nitrite accumulation (ED 50 of 1.38 and 22.2 μmol kg −1 , respectively) and release of the chemokine KC (ED 50 of 5.5 and 27.7 μmol kg −1 , respectively) as determined at the 4 h time‐point. No differences were measured for the levels of interleukin‐1β or prostaglandin E 2 . NCX‐1015 administered orally was also found to be equally active. Co‐administration of the nitric oxide donors NOC‐18 ((z)‐1‐[(2‐aminoethyl)‐N‐(2‐aminoethyl)amino] diazen‐1‐ium‐1, 2‐diolate; 7.9 μmol kg −1 ) or sodium nitroprusside (13.8 μmol kg −1 ) with prednisolone resulted in an additive anti‐migratory action. In a chronic model of granulomatous tissue inflammation, administration of NCX‐1015 (13.9 μmol kg −1 ) from day 1 (i.e. after induction of inflammation) was more effective than prednisolone in reducing the granuloma dry weight, and this was associated to a lower anti‐angiogenic effect. In conclusion we show that NCX‐1015 is more potent than prednisolone in controlling several, though not all, parameters of acute and chronic inflammation, and propose that this effect may be due to a co‐operation between the steroid moiety and nitric oxide or related species released in biological fluids. Whereas this aspect needs to be further clarified, we propose NCX‐1015 as the first member of a novel class of anti‐inflammatory compounds, the nitro‐steroids.British Journal of Pharmacology (2000) 131 , 1345–1354; doi: 10.1038/sj.bjp.0703704