The protective role of estrogen-receptor-beta in retinal excitotoxicity.

The likelihood that 17beta-estradiol (E2) may exert its neuroprotective actions in retinal diseases is going to be considered on the evidence of its beneficial effects in retinal ischemia, light-induced photoreceptor degeneration, retinitis pigmentosa, AMD and experimental glaucoma. Recently, we have showed E2 synthesis in the adult male retina and identified the estrogen-synthesizing aromatase enzyme primarily located in the outer plexiform and inner nuclear layers, thus substantiating the role of E2 in the retina as well as in brain, independently of sex. Furthermore, both estrogen receptor subtypes, ERalpha and ERbeta, were found throughout the retina with the highest intensity in the inner retina. To explore whether retinal excitotoxic insult may interfere with E2 synthesis and function, we examined the expression and activity of aromatase and ERalpha and ERbeta in retinal explants of adult male rats exposed to NMDA receptor-mediated toxicity. We found that insulted retinas had a low level of E2, a reduced ability in converting testosterone into E2 and an unchanged expression of aromatase; however, blockers of NMDA receptor-induced calcium influx restored E2 levels. Expressions of ERalfa and ERbeta were respectively reduced and enhanced, and the exogenous application of E2 prevented only ERalpha reduction. After the excitotoxic insult, a selective ERbeta ligand was most effective in halting retinal toxicity when compared to ERalpha-mediated protective effects observed only at micromolar E2 concentrations. These results suggest that retinal NMDA receptor-induced calcium-mediated mechanisms interfere with aromatase activity and affect endogenous E2 synthesis, this may result in a different regulation of estrogen receptors and a favoured ERbeta function.