Background: Mapracorat, a novel nonsteroidal selective glucocorticoid receptor agonist, has been proposed for the topical treatment of infammatory disorders as it binds with high affnity and selectivity to the human glucocorticoid receptor and displays a potent anti-infammatory 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 infltration 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 proinfammatory 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 infltra-tion, 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. Conclusion: 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.

Mapracorat, a selective glucocorticoid receptor agonist, causes apoptosis of eosinophils infiltrating the conjunctiva in late phase experimental ocular allergy / Baiula M; Bedini A; Baldi J; Govoni P; Spampinato S. - In: DRUG DESIGN, DEVELOPMENT AND THERAPY. - ISSN 1177-8881. - STAMPA. - 8:(2014), pp. 745-757. [10.2147/DDDT.S6265]

Mapracorat, a selective glucocorticoid receptor agonist, causes apoptosis of eosinophils infiltrating the conjunctiva in late phase experimental ocular allergy

BAIULA, MONICA;BEDINI, ANDREA;GOVONI, PAOLO;SPAMPINATO, SANTI MARIO
2014

Abstract

Background: Mapracorat, a novel nonsteroidal selective glucocorticoid receptor agonist, has been proposed for the topical treatment of infammatory disorders as it binds with high affnity and selectivity to the human glucocorticoid receptor and displays a potent anti-infammatory 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 infltration 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 proinfammatory 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 infltra-tion, 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. Conclusion: 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.
2014
Mapracorat, a selective glucocorticoid receptor agonist, causes apoptosis of eosinophils infiltrating the conjunctiva in late phase experimental ocular allergy / Baiula M; Bedini A; Baldi J; Govoni P; Spampinato S. - In: DRUG DESIGN, DEVELOPMENT AND THERAPY. - ISSN 1177-8881. - STAMPA. - 8:(2014), pp. 745-757. [10.2147/DDDT.S6265]
Baiula M; Bedini A; Baldi J; Govoni P; Spampinato S
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/395812
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