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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, Cavet ME, Govoni P, Spampinato S - Drug Des Devel Ther (2014)

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.

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.

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.

No MeSH data available.


Related in: MedlinePlus

Map and Dex (0.4%; w/v) eye drops do not cause any apparent increase in the number of positive apoptotic eosinophils detected by TUNEL procedure in tarsal conjunctival sections prepared from guinea pigs sacrificed 6 hours after Map and Dex treatment (8 hours after OVA challenge).Notes: Contrary to apoptotic eosinophils, non-apoptotic eosinophils infiltrating the conjunctiva, evidenced by chromotrope-2R, were increased by OVA challenge and reduced by Map and Dex. Ctrls were not treated with OVA. Representative micrographs, in which TUNEL-positive cells appear as distinct, rounded, bright green nuclei and chromotrope-2R-positive cells appear as red spots, are shown. Each group comprised five guinea pigs, and both eyes were evaluated (n=10).Abbreviations: Ctrl, control; Dex, dexamethasone; Map, mapracorat; OVA, ovalbumin; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling.
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f7-dddt-8-745: Map and Dex (0.4%; w/v) eye drops do not cause any apparent increase in the number of positive apoptotic eosinophils detected by TUNEL procedure in tarsal conjunctival sections prepared from guinea pigs sacrificed 6 hours after Map and Dex treatment (8 hours after OVA challenge).Notes: Contrary to apoptotic eosinophils, non-apoptotic eosinophils infiltrating the conjunctiva, evidenced by chromotrope-2R, were increased by OVA challenge and reduced by Map and Dex. Ctrls were not treated with OVA. Representative micrographs, in which TUNEL-positive cells appear as distinct, rounded, bright green nuclei and chromotrope-2R-positive cells appear as red spots, are shown. Each group comprised five guinea pigs, and both eyes were evaluated (n=10).Abbreviations: Ctrl, control; Dex, dexamethasone; Map, mapracorat; OVA, ovalbumin; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling.

Mentions: As previously stated in this paper, late-phase allergic reaction is characterized by conjunctival eosinophil infiltration that starts 4 hours after allergen challenge. To investigate if apoptotic eosinophils are detected in the conjunctiva as early as 8 hours after OVA challenge, we performed a separate experiment in which we observed that mapracorat or dexamethasone (0.4%) did not elevate the number of TUNEL-positive cells in conjunctival specimens of OVA-challenged guinea pigs sacrificed 6 hours after drug treatment (8 hours after OVA), although a significant number of infiltrating chromotrope-2R-positive eosinophils was evidenced (Figure 7). Thus, eosinophil apoptosis induced by glucocorticoid receptor agonists is a late event that has been detected 22 hours after drug treatment and has also been observed in human eosinophils cultured in vitro for at least 24 hours.18


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, Cavet ME, Govoni P, Spampinato S - Drug Des Devel Ther (2014)

Map and Dex (0.4%; w/v) eye drops do not cause any apparent increase in the number of positive apoptotic eosinophils detected by TUNEL procedure in tarsal conjunctival sections prepared from guinea pigs sacrificed 6 hours after Map and Dex treatment (8 hours after OVA challenge).Notes: Contrary to apoptotic eosinophils, non-apoptotic eosinophils infiltrating the conjunctiva, evidenced by chromotrope-2R, were increased by OVA challenge and reduced by Map and Dex. Ctrls were not treated with OVA. Representative micrographs, in which TUNEL-positive cells appear as distinct, rounded, bright green nuclei and chromotrope-2R-positive cells appear as red spots, are shown. Each group comprised five guinea pigs, and both eyes were evaluated (n=10).Abbreviations: Ctrl, control; Dex, dexamethasone; Map, mapracorat; OVA, ovalbumin; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061172&req=5

f7-dddt-8-745: Map and Dex (0.4%; w/v) eye drops do not cause any apparent increase in the number of positive apoptotic eosinophils detected by TUNEL procedure in tarsal conjunctival sections prepared from guinea pigs sacrificed 6 hours after Map and Dex treatment (8 hours after OVA challenge).Notes: Contrary to apoptotic eosinophils, non-apoptotic eosinophils infiltrating the conjunctiva, evidenced by chromotrope-2R, were increased by OVA challenge and reduced by Map and Dex. Ctrls were not treated with OVA. Representative micrographs, in which TUNEL-positive cells appear as distinct, rounded, bright green nuclei and chromotrope-2R-positive cells appear as red spots, are shown. Each group comprised five guinea pigs, and both eyes were evaluated (n=10).Abbreviations: Ctrl, control; Dex, dexamethasone; Map, mapracorat; OVA, ovalbumin; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling.
Mentions: As previously stated in this paper, late-phase allergic reaction is characterized by conjunctival eosinophil infiltration that starts 4 hours after allergen challenge. To investigate if apoptotic eosinophils are detected in the conjunctiva as early as 8 hours after OVA challenge, we performed a separate experiment in which we observed that mapracorat or dexamethasone (0.4%) did not elevate the number of TUNEL-positive cells in conjunctival specimens of OVA-challenged guinea pigs sacrificed 6 hours after drug treatment (8 hours after OVA), although a significant number of infiltrating chromotrope-2R-positive eosinophils was evidenced (Figure 7). Thus, eosinophil apoptosis induced by glucocorticoid receptor agonists is a late event that has been detected 22 hours after drug treatment and has also been observed in human eosinophils cultured in vitro for at least 24 hours.18

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.

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.

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.

No MeSH data available.


Related in: MedlinePlus