title: Suppressive effects of nitric oxide-releasing prednisolone NCX-1015 on the allergic pleural eosinophil recruitment in rats.
abstract: BACKGROUND
  The addition of a nitric oxide (NO)-releasing moiety to prednisolone was shown to enhance the anti-inflammatory activity of this glucocorticoid in some experimental conditions, but its effectiveness in the context of eosinophilic inflammation remains to be elucidated.
  
  
  OBJECTIVE
  This study compared the anti-inflammatory effect of prednisolone to a NO-releasing derivative of prednisolone, NCX-1015, using a model of allergen-evoked eosinophil recruitment in rats. The efficacy of a NO-donor compound, DETA-NONOate, was also assessed for comparison.
  
  
  METHODS
  Wistar rats were actively sensitized with Al(OH)(3) plus ovalbumin and 14 days later challenged with antigen intrapleurally. Treatments were performed locally 1 h before challenge. Cysteinyl-leucotrienes (Cys-LT) and eotaxin were measured by ELISA.
  
  
  RESULTS
  Antigen challenge induced an eosinophil infiltration at 12 h, maximal at 24 h. It also caused an increase in the levels of Cys-LTs in the pleural exudate and in the expression of 5-lipoxygenase (5-LO) in infiltrated leucocytes at 6 h, peaking at 12 h and persisting for at least 24 h. Treatment with equimolar doses of prednisolone and NCX-1015 inhibited the late eosinophil infiltration, although the dose required to produce maximal inhibition was about one-tenth that of prednisolone. Cys-LT generation and 5-LO expression were inhibited by NCX-1015 but not by prednisolone. Treatment with prednisolone combined with the NO-donor DETA-NONOate led to a greater inhibition of the eosinophilia and Cys-LT generation as compared with either drug alone. Administration of the steroid receptor antagonist RU 486, 1 h before prednisolone and NCX-1015, abolished the inhibitory effect of the former, under conditions where it only partially affected the latter.
  
  
  CONCLUSIONS
  Our findings indicate that NCX-1015 provided a greater anti-inflammatory effect than prednisolone on the allergic eosinophil recruitment in rats, suggesting that NO-releasing steroids can be considered as a promising therapeutic approach to allergic diseases.
authors.affiliation: Laboratório de Inflamação, Instituto Oswaldo Cruz, FIOCRUZ, Manguinhos, Rio de Janeiro, Brazil.
authors.forename: M S S
authors.initials: MS
authors.lastname: Oliveira
authors.forename: E
authors.initials: E
authors.lastname: de O Barreto
authors.forename: S
authors.initials: S
authors.lastname: Zamuner
authors.forename: A L A
authors.initials: AL
authors.lastname: Pires
authors.forename: T P T
authors.initials: TP
authors.lastname: Ferreira
authors.forename: R S B
authors.initials: RS
authors.lastname: Cordeiro
authors.forename: V
authors.initials: V
authors.lastname: Lagente
authors.forename: M A
authors.initials: MA
authors.lastname: Martins
authors.forename: J L
authors.initials: JL
authors.lastname: Wallace
authors.forename: P M R
authors.initials: PM
authors.lastname: e Silva
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D054413:Chemokine CCL11 / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004802:Eosinophilia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004804:Eosinophils / Q000166:cytology; D006967:Hypersensitivity / Q000150:complications* / Q000188:drug therapy; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D015289:Leukotrienes / Q000378:metabolism; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology; D020030:Nitric Oxide Donors / Q000627:therapeutic use*; D009603:Nitroso Compounds / Q000627:therapeutic use; D010047:Ovalbumin / Q000276:immunology; D035422:Pleural Cavity / Q000378:metabolism / Q000473:pathology; D010998:Pleurisy / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D011239:Prednisolone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D015289:Leukotrienes; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D011965:Receptors, Glucocorticoid; C112381:cysteinyl-leukotriene; C418962:prednisolone 21-((4'-nitrooxymethyl)benzoate); C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D015735:Mifepristone; D010047:Ovalbumin; D011239:Prednisolone; D001094:Arachidonate 5-Lipoxygenase; D003545:Cysteine