Anti‐inflammatory mechanisms of mapracorat, a novel selective glucocorticoid receptor agonist, in human conjunctival fibroblasts

Abstract

AbstractPurpose Mapracorat (BOL‐303242‐X; ZK 245186) is a selective glucocorticoid receptor agonist (SEGRA), under clinical evaluation for the treatment of inflammatory eye and skin diseases. It is structurally distinct from glucocorticoids and NSAIDs. Data suggest an improved side effect profile of this compound compared to traditional glucocorticoids. This study was to determine its anti‐inflammatory mechanisms.Methods Primary human conjunctival fibroblasts (HConF)were challenged with IL‐1ß and Luminex technology or ELISA was used to determine the effect of mapracorat on IL‐1ß‐induced cytokine, prostaglandin E2 (PGE2) and matrix metalloproteinase (MMP) release in the presence or absence of mifepristone (RU‐486), a glucocorticoid receptor antagonist. The effect of mapracorat on IL‐1ß‐induced cyclooxygenase‐2 (COX‐2) expression was assessed by Western blotting. Dexamethasone was used as the control.Results IL‐1ß induced release of multiple cytokines, including IL‐6, IL‐8 and monocyte chemotactic protein‐1 (MCP‐1), and of PGE2 and MMPs (MMP‐1 and MMP‐3), as well as the expression of COX‐2. Mapracorat inhibited cytokine, PGE2 and MMP release as well as COX‐2 expression in a dose‐dependent manner with comparable effectiveness as dexamethasone. The inhibition of cytokine and PGE2 release was fully or partially reversed by mifepristone.Conclusion Mapracorat acts as a potent anti‐inflammatory agent in HConF by inhibiting multiple intracellular mediators. The fact that mapracorat is effective on inhibiting PGE2 pathway suggests that it may reduce post‐surgery pain. Clinical significance of these findings needs further investigation. Commercial interest