Steroid hormones and photoreceptor survival.

SUBURO, AM

Montevideo

Simposio; Symposium Development and Plasticity of the Nervous System; 2010

IIBCE y Facultad de Ciencias, Montevideo, Uruguay (PEDECIBA, AMSUD-Pasteur, IBRO-LARC, ANII)

Steroid Hormones and Photoreceptor survival Angela M Suburo. Facultad de Ciencias Biomédicas, Universidad Austral and CONICET, Argentina. amsuburo@cas.austral.edu.ar Purpose: Glucocorticoids (GCs) secreted from the adrenal cortex easily pass through the blood brain barrier and bind to intracellular glucocorticoid (GRα) receptors in neurons and glia. They are critical for survival and viability in conditions that defy the future of neurons, such as neurodegenerative conditions. GCs prevent light-induced and inherited retinal degeneration. GRα agonists are increasingly used in different retinal diseases, and antagonists such as mifepristone (MFP) have been advocated for treatment of serous chorioretinopathy. Therefore we need a deeper understanding of the GC pathways involved in photoreceptor survival. Methods: Male Balb-c mice were exposed to 1,500 lux during 2 or 4 days. Light-exposed and non-exposed mice received MFP with or without dexamethasone (DEX). GRα, rhodopsin (RHO), the executor caspase, cleaved caspase-3 (CC-3), and the antiapoptic protein Bcl-XL were studied by immunohistochemistry and Western blotting. Results: Light exposure increased GR immunoreactivity in photoreceptor nuclei and decreased RHO levels. RHO levels were much lower in the presence of MFP. DEX maintained RHO levels, even in the presence of MFP. Light-induced damage was accompanied by appearance of CC-3 and depletion of Bcl-XL, an antiapoptotic member of the Bcl2 family. DEX blocked caspase-3 activation and increased Bcl-XL. MFP administration during light exposure resulted in higher levels of CC-3. When MFP was given, caspase-3 activation was only partially reversed and Bcl-XL disappearance was no prevented by DEX. Conclusions: Increase of nuclear GRα in retinas subjected to 1,500 lux indicates that GRα nuclear signaling contributes to the photoreceptor damage response. The most likely explanation is a build-up of endogenous ligands in light-stressed retinas, but GR transcription and translation might be also upregulated. MFP aggravated light-induced damage. The larger RHO depletion could reflect a sensibilization of the OS to light, or perhaps a decrease in RHO expression. DEX administration effectively protected RHO levels, but was only partially successful in reversing the MFP-induced proapoptotic conditions: low Bcl-XL and high CC-3. These MFP effects would only be partially associated to GRα inhibition and might be explained by MFP binding to progesterone receptors.