Steroids and photoreceptor survival in two models of retinal degeneration

TATE P.S; MARQUIONI RAMELLA M.D; SUBURO A.M; MARAZITA M.C

Vancouver

Congreso; The Association for Research in Vision and Ophthalmology (ARVO); 2019

Visual loss in degenerating retinal diseases usually implies photoreceptor loss. Current evidence shows that glucocorticoids and progestogens enhance photoreceptor survival. By contrast, mifepristone (M), a glucocorticoid and progesterone receptor blocker, induces photoreceptor death. To understand the steroid-dependent mechanisms involved in photoreceptor survival, we compared the effect of dexamethasone (D) and progesterone (P) in light- and M-induced retinal degeneration models. For retinal damage, male BALB/c mice (5-7 weeks) received a single 10 mg/kg M injection, or they were exposed to 1500 lux during 48 h. Steroid treated animals received 4 mg/kg/day D or 1-4 mg/kg/day P for two days. Control mice were given 0.9% NaCl. Animals were euthanized after 48 h and retinas were prepared for Western blot (WB) or histochemical procedures. Some animals were euthanized in day 7 and their eyes sectioned to measure the thickness of the outer nuclear layer (ONL).Activated caspase 3 (CASP3) immunohistochemistry and TUNEL showed that signs of cell death were restricted to the ONL. Day 7 histological sections showed only 43% and 35% photoreceptor nuclei survived M or 1500 lux, respectively. However, 4 mg/kg D or P preserved >90% photoreceptor nuclei in both models. WBs showed similar changes of cell death and survival markers in both models. CASP3 disappeared when mice were treated with D or P, whereas phosphorylated histone H2AX (p-H2AX) was greatly reduced. BCL-XL, BAX and BID responded similarly to each steroid in both degenerating models. By contrast, BCL2 disappeared in M-treated mice but increased above control levels in treated light-exposed mice. Most important, the steroid survival responses could be correlated with D and P effects on BCL-XL, BAX and BID levels in undamaged animals. In addition, the latter mice showed significant rhodopsin increases after steroid treatment. Results show that M and excessive light killed a similar proportion of photoreceptors. Similarly, both P and D were efficient photoreceptor protectors in both models. In addition, the effect of these steroids on cell death regulators, together with the photoreceptor attrition triggered by the inhibition of glucocorticoid and progestogens receptors strongly suggest that these hormones are essential for the survival of photoreceptors even under standard illumination conditions.