title: 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.
authors.affiliation: Department of Biochemical Pharmacology, St Bartholomew's and the Royal London School of Medicine and Dentistry, London.
authors.forename: M
authors.initials: M
authors.lastname: Paul-Clark
authors.forename: P
authors.initials: P
authors.lastname: Del Soldato
authors.forename: S
authors.initials: S
authors.lastname: Fiorucci
authors.forename: R J
authors.initials: RJ
authors.lastname: Flower
authors.forename: M
authors.initials: M
authors.lastname: Perretti
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis / Q000187:drug effects; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006099:Granuloma / Q000517:prevention & control; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D007375:Interleukin-1 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000517:prevention & control; D011239:Prednisolone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000187:drug effects; D016896:Treatment Outcome; D015054:Zymosan / Q000009:adverse effects; D000098902:CD163 Antigen
chemical_list: D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D007375:Interleukin-1; D011956:Receptors, Cell Surface; C418962:prednisolone 21-((4'-nitrooxymethyl)benzoate); D009569:Nitric Oxide; D015054:Zymosan; D011239:Prednisolone