title: Mapracorat, a selective glucocorticoid receptor agonist, causes apoptosis of eosinophils infiltrating the conjunctiva in late-phase experimental ocular allergy.
abstract: BACKGROUND
  Mapracorat, a novel nonsteroidal selective glucocorticoid receptor agonist, has been proposed for the topical treatment of inflammatory disorders as it binds with high affinity and selectivity to the human glucocorticoid receptor and displays a potent anti-inflammatory activity, but seems to be less effective in transactivation of a number of genes, resulting in a lower potential for side effects. Contrary to classical glucocorticoids, mapracorat displays a reduced ability to increase intraocular pressure and in inducing myocilin, a protein linked to intraocular pressure elevation. Allergic conjunctivitis is the most common form of ocular allergy and can be divided into an early phase, developing immediately after allergen exposure and driven primarily by mast cell degranulation, and a late phase, developing from 6-10 hours after the antigen challenge, and characterized by conjunctival infiltration of eosinophils and other immune cells as well as by the production of cytokines and chemokines.
  
  
  METHODS
  In this study, mapracorat was administered into the conjunctival sac of ovalbumin (OVA)-sensitized guinea pigs 2 hours after the induction of allergic conjunctivitis, with the aim of investigating its activity in reducing clinical signs of the late-phase ocular reaction and to determine its mechanism of anti-allergic effects with respect to apoptosis of conjunctival eosinophils and expression of the chemokines C-C motif ligand 5 (CCL5), C-C motif ligand 11 (CCL11), and interleukin-8 (IL-8) and the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α).
  
  
  RESULTS
  Mapracorat, administered into the conjunctival sac of OVA-sensitized guinea pigs 2 hours after allergen exposure, was effective in reducing clinical signs, eosinophil infiltration, and eosinophil peroxidase activity in the guinea pig conjunctiva; furthermore, it reduced conjunctival mRNA levels and protein expression of both CCL5 and CCL11. Mapracorat was more effective than dexamethasone in increasing, in conjunctival sections of OVA-treated guinea pigs, apoptotic eosinophils.
  
  
  CONCLUSIONS
  Mapracorat displays anti-allergic properties in controlling the late phase of ocular allergic conjunctivitis and is a promising candidate for the topical treatment of allergic eye disorders.
authors: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors: Monica
authors: M
authors: Baiula
authors: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors: Andrea
authors: A
authors: Bedini
authors: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors: Jacopo
authors: J
authors: Baldi
authors: Global Pharmaceutical R&D, Bausch & Lomb Inc., Rochester, NY, USA.
authors: Megan E
authors: ME
authors: Cavet
authors: Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Parma, Italy.
authors: Paolo
authors: P
authors: Govoni
authors: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors: Santi
authors: S
authors: Spampinato
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D003228:Conjunctiva / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D003233:Conjunctivitis, Allergic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004804:Eosinophils / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008968:Molecular Conformation; D000439:Pentanols / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; D000439:Pentanols; D011804:Quinolines; C546413:R-1,1,1-trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-(((2-methyl-5-quinolyl)amino)methyl)pentan-2-ol; D011965:Receptors, Glucocorticoid
keywords: allergic conjunctivitis; eosinophil; late-phase response