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Enhanced anti‐inflammatory potency of a nitric oxide‐releasing prednisolone derivative in the rat
Author(s) -
Turesin Fusun,
Del Soldato Piero,
Wallace John L
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705324
Subject(s) - chemistry , nitric oxide synthase , nitric oxide , carrageenan , pharmacology , prednisolone , potency , cyclooxygenase , nitrite , inflammation , endocrinology , biochemistry , medicine , enzyme , in vitro , organic chemistry , nitrate
Derivatization of nonsteroidal anti‐inflammatory drugs, such that they release nitric oxide (NO) in small amounts, has been shown to significantly increase their anti‐inflammatory activity and analgesic potency. In this study, we compared the anti‐inflammatory potency of prednisolone to a nitric oxide‐releasing derivative of prednisolone (NCX‐1015). Carrageenan‐induced inflammation of an airpouch in the rat was used. The rats were pretreated with equimolar doses of prednisolone or NCX‐1015 and the effects on leukocyte infiltration into the airpouch and exudates levels of prostaglandin E 2 (PGE 2 ), leukotriene B 4 (LTB 4 ) and nitrite (as an index of NO production) were measured 6 h later. Injection of carrageenan into the airpouch resulted in a progressive increase in leukocyte infiltration, and accumulation of PGE 2 , LTB 4 and nitrite. Carrageenan also induced elevated expression of cyclooxygenase‐1 and ‐2, inducible nitric oxide synthase and 5‐lipoxygenase in the inflammatory exudate. Prednisolone dose dependently reduced the numbers of leukocytes within the airpouch exudates, as well as reducing PGE 2 , LTB 4 and nitrite levels. NCX‐1015 also reduced leukocyte numbers and inflammatory mediator levels. However, the doses of NCX‐1015 required to produce a maximal reduction of each of these parameters was one‐third to one‐tenth the dose of prednisolone that produced a comparable effect. The reduction of PGE 2 and NO production was likely to be at least in part due to reduced expression of the key enzymes responsible for their synthesis (cyclooxygenase‐2, inducible NO synthase), with NCX‐1015 producing greater suppression than prednisolone at an equimolar dose. Coadministration of prednisolone with a nitric oxide donor (DETA‐NONOate) resulted in a greater reduction of leukocyte infiltration and inflammatory mediator production than was observed with either drug alone. These results support the notion that delivery of NO to a site of inflammation can markedly enhance the anti‐inflammatory activity of a glucocorticoid.British Journal of Pharmacology (2003) 139 , 966–972. doi: 10.1038/sj.bjp.0705324