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

Abstract 1. 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 microM) 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 micromol kg(-1)) produced nitrite accumulation in the peritoneal cavity maximal at 60 min. 2. 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-1 beta release from these cells was inhibited by NCX-1015 with higher potency than prednisolone. 3. In the zymosan peritonitis model, NCX-1015 was more active than prednisolone in suppressing neutrophil extravasation (ED(50) of 5.5 and 25.8 micromol kg(-1), respectively), nitrite accumulation (ED(50) of 1.38 and 22.2 micromol kg(-1), respectively) and release of the chemokine KC (ED(50) of 5.5 and 27.7 micromol kg(-1), respectively) as determined at the 4 h time-point. No differences were measured for the levels of interleukin-1 beta 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 micromol kg(-1)) or sodium nitroprusside (13.8 micromol kg(-1)) with prednisolone resulted in an additive anti-migratory action. 4. In a chronic model of granulomatous tissue inflammation, administration of NCX-1015 (13.9 micromol 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. 5. 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.