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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 eye drops increase, in a dose-related manner, the number of positive apoptotic cells evaluated by the TUNEL technique in tarsal conjunctival sections prepared from guinea pigs sacrificed 24 hours after OVA challenge.Notes: Ctrls received the vehicle alone and were not treated with topical OVA. (A) Representative micrographs. Apoptotic cells appear rounded and bright green. Nuclei were counterstained with DAPI. (B) Values are the mean ± standard error of the mean (n=10; both eyes of five guinea pigs were evaluated). *P<0.05, §P<0.01 versus OVA + vehicle; #P<0.01 versus Dex at the same dose (one-way ANOVA with Newman-Keuls post test). Scale bar equals 50 μm.Abbreviations: Ctrl, control; DAPI, 4′,6-diamidino-2-phenylindole; Dex, dexamethasone; Map, mapracorat; OVA, ovalbumin; TUNEL, terminal deoxynu cleotidyl transferase dUTP nick end labeling.
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f5-dddt-8-745: Map and Dex eye drops increase, in a dose-related manner, the number of positive apoptotic cells evaluated by the TUNEL technique in tarsal conjunctival sections prepared from guinea pigs sacrificed 24 hours after OVA challenge.Notes: Ctrls received the vehicle alone and were not treated with topical OVA. (A) Representative micrographs. Apoptotic cells appear rounded and bright green. Nuclei were counterstained with DAPI. (B) Values are the mean ± standard error of the mean (n=10; both eyes of five guinea pigs were evaluated). *P<0.05, §P<0.01 versus OVA + vehicle; #P<0.01 versus Dex at the same dose (one-way ANOVA with Newman-Keuls post test). Scale bar equals 50 μm.Abbreviations: Ctrl, control; DAPI, 4′,6-diamidino-2-phenylindole; Dex, dexamethasone; Map, mapracorat; OVA, ovalbumin; TUNEL, terminal deoxynu cleotidyl transferase dUTP nick end labeling.

Mentions: OVA challenge did not cause any significant elevation of apoptotic, TUNEL-positive cells lying scattered in the conjunctival tissue in comparison to controls at a 24-hour time point (Figure 5). Interestingly, we observed that mapracorat and dexamethasone, administered 2 hours after OVA, were effective in increasing, in a dose-related manner, the number of apoptotic TUNEL-positive cells in guinea pig conjunctiva in comparison to OVA-treated animals. Mapracorat eye drops caused a more marked conjunctival cell apoptosis compared to the same dose of dexamethasone (Figure 5).


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 eye drops increase, in a dose-related manner, the number of positive apoptotic cells evaluated by the TUNEL technique in tarsal conjunctival sections prepared from guinea pigs sacrificed 24 hours after OVA challenge.Notes: Ctrls received the vehicle alone and were not treated with topical OVA. (A) Representative micrographs. Apoptotic cells appear rounded and bright green. Nuclei were counterstained with DAPI. (B) Values are the mean ± standard error of the mean (n=10; both eyes of five guinea pigs were evaluated). *P<0.05, §P<0.01 versus OVA + vehicle; #P<0.01 versus Dex at the same dose (one-way ANOVA with Newman-Keuls post test). Scale bar equals 50 μm.Abbreviations: Ctrl, control; DAPI, 4′,6-diamidino-2-phenylindole; Dex, dexamethasone; Map, mapracorat; OVA, ovalbumin; TUNEL, terminal deoxynu cleotidyl transferase dUTP nick end labeling.
© Copyright Policy
Related In: Results  -  Collection

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

f5-dddt-8-745: Map and Dex eye drops increase, in a dose-related manner, the number of positive apoptotic cells evaluated by the TUNEL technique in tarsal conjunctival sections prepared from guinea pigs sacrificed 24 hours after OVA challenge.Notes: Ctrls received the vehicle alone and were not treated with topical OVA. (A) Representative micrographs. Apoptotic cells appear rounded and bright green. Nuclei were counterstained with DAPI. (B) Values are the mean ± standard error of the mean (n=10; both eyes of five guinea pigs were evaluated). *P<0.05, §P<0.01 versus OVA + vehicle; #P<0.01 versus Dex at the same dose (one-way ANOVA with Newman-Keuls post test). Scale bar equals 50 μm.Abbreviations: Ctrl, control; DAPI, 4′,6-diamidino-2-phenylindole; Dex, dexamethasone; Map, mapracorat; OVA, ovalbumin; TUNEL, terminal deoxynu cleotidyl transferase dUTP nick end labeling.
Mentions: OVA challenge did not cause any significant elevation of apoptotic, TUNEL-positive cells lying scattered in the conjunctival tissue in comparison to controls at a 24-hour time point (Figure 5). Interestingly, we observed that mapracorat and dexamethasone, administered 2 hours after OVA, were effective in increasing, in a dose-related manner, the number of apoptotic TUNEL-positive cells in guinea pig conjunctiva in comparison to OVA-treated animals. Mapracorat eye drops caused a more marked conjunctival cell apoptosis compared to the same dose of dexamethasone (Figure 5).

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