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Jin-Zhong Zhang, Sherry L. Spinelli, Xia Xi, Steven E. Feldon, Richard P. Phipps; A Distinctive Anti-inflammatory Mechanism In Human Ocular Cells Associated With Mapracorat, A Novel Selective Glucocorticoid Receptor Agonist. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2350.
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Selective glucocorticoid receptor agonists (SEGRAs) are a new therapeutic class of potent anti-inflammatory agents, structurally and functionally distinct from steroids and non-steroidal anti-inflammatory drugs (NSAIDs). Mapracorat (BOL-303242-X; ZK 245186) is a novel SEGRA under clinical evaluation for the treatment of inflammatory eye and skin diseases. Ocular inflammation is associated with increased activity of proinflammatory transcription factors, such as Nuclear Factor-kappaB (NF-ΚB). Regulation of NF-ΚB is controlled by classical and alternative pathways. Our hypothesis is that mapracorat exerts its unique effects by upregulating components of the anti-inflammatory alternative NF-ΚB pathway and by downregulating components of the classical proinflammatory NF-ΚB pathway.
Western blotting was performed for key NF-ΚB family members, RelA (p65), RelB, Inhibitor kappa kinases (IKKs) and others, to assess the changes in protein levels associated with mapracorat in primary human ocular cell types, including corneal epithelial cells, corneal fibroblasts and conjunctival fibroblasts. A range of mapracorat doses were tested at different time points in the absence and presence of a provoking agent (IL-1β). In parallel, cells were treated with a classical steroid, dexamethasone, for comparison.
Mapracorat at low nanomolar concentrations not only increased RelB protein, but also activation of other members of the "anti-inflammatory" alternative pathway such as IKKα, following IL-1β treatment, with superior effects compared to dexamethasone. Concomitantly, there was also a reduction in the levels of phosphorylated RelA (p65), an inflammation-associated NF-ΚB family member.
Data suggest that mapracorat exerts its anti-inflammatory effects in part by increasing anti-inflammatory mediators, including RelB, that are part of the alternative NF-ΚB pathway, and by decreasing classical inflammatory mediators of NF-ΚB, including RelA (p65). Upregulation of RelB and the alternative NF-ΚB pathway represents an unexpected and novel anti-inflammatory mechanism of action for mapracorat.
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