Mifepristone, a Blocker of Glucocorticoid Receptors, Promotes Photoreceptor Death

Abstract

PURPOSE. Glucocorticoids are best known by their protective effect on retinal photoreceptor damage. However, they could also be involved in photoreceptor homeostasis under basal, nonstressful conditions. Therefore, we aimed to study glucocorticoid-induced changes of survival-related molecules in male mice retinas under standard illumination conditions (12 hours light, 60 lux/12 h dark).METHODS. Male Balb-c mice were injected with dexamethasone (DEX), a selective glucocorticoid receptor a (GRa) agonist, its antagonist mifepristone (MFP), or both drugs (DþM) at noon. A group of mice was subjected to surgical adrenalectomy (AdrX). Retinas were studied by histology, immunohistochemistry, TUNEL procedure, and Western blotting at different periods after pharmacological or surgical intervention (6 hours, 48 hours, or 7 days). RESULTS.The antiapoptotic molecule Bcl-X L significantly increased 6 hours after DEX injection. By contrast, this molecule could no longer be found after MFP injection. At the same time, high levels of cleaved caspase-3 (CC-3) and Bax appeared in retinal extracts, and TUNEL þ nuclei selectively showed in the outer nuclear layer (ONL). After MFP, retinal extracts also contained phosphorylated histone H2AX (p-H2AX), a marker of DNA breakage and repair. Loss of ONL nuclear rows and decrease of rhodopsin levels were evident 7 days after MFP administration. These changes were minimized when DEX was given together with MFP (DþM). In the absence of MFP, DEX increased Bcl-X L in every retinal layer, with a marked intensification in photoreceptor inner segments. Numerous TUNEL þ nuclei rapidly appeared in the ONL after AdrX. CONCLUSIONS.A single dose of MFP induced selective photoreceptor damage in the absence of other environmental stressors. Because damage was prevented by DEX, and was reproduced by AdrX, our findings suggest that glucocorticoids play a critical role in photoreceptor survival. (Invest Ophthalmol Vis Sci. 2013;54:313-322)

Glucocorticoid receptor signaling in health and disease

“…Response to glucocorticoid treatment in the eye implies a natural role for glucocorticoid signaling in the eye. Furthermore, by using rodent models, it has been shown that glucocorticoids confer protection in photoreceptors in the retina by preventing their apoptosis [53, 54]. …”

Steroid and Xenobiotic Receptor Signalling in Apoptosis and Autophagy of the Nervous System

“…In contrast, MR overexpression inhibited apoptosis and promoted survival of embryonic stem cell-derived neurons [ 84 ]. Unlike in other brain regions, glucocorticoids play a critical role in retinal photoreceptor survival, whereas mifepristone, which has the capacity to block glucocorticoid receptors, promotes photoreceptor death [ 85 ]. Furthermore, an MR agonist aldosterone appeared to be a critical mediator of retinal ganglion cell loss that was independent of elevated intraocular pressure [ 86 ].…”

Association of Caspase 3 Activation and H2AX γ Phosphorylation in the Aging Brain: Studies on Untreated and Irradiated Mice

“…Studies in neurons, on the other hand, have not primarily focused on the links between H2AX and apoptosis. They aimed, instead, to assess the response of isolated cells or the intact brain to several DNA-damaging agents of heterogeneous nature (e.g., hydrogen peroxide [ 10 ] and mifepristone [ 11 ]) that have been reported to induce γH2AX with [ 11 ] or without [ 10 ] the concomitant activation of CASP3.…”