Estrogens and neuroprotection in retinal diseases

Abstract

Estrogens play a critical role in the normal growth and development of humans and in recent years our understanding of their effects in the central nervous system (CNS) have been advancing rapidly. It is now known that estrogens influence synaptic plasticity, brain development, and memory. In addition, estrogens have been shown to be neuroprotective in degenerative disorders. The understanding of the influences of estrogens in the retina, as a component of the CNS, has not kept pace with the advances in understanding of the brain. Studies that have addressed the effects of estrogens on the retina, specifically those focusing on glaucoma, are examined here in the hope that estrogen therapy may be a viable option for treating retinal dystrophies and optic neuropathies.

Figure 1

Termination, stabilization, and recycling of free-radical by phenolic estrogen derived drugs. Structure A represents the quinolic ring that can spontaneously convert to a phenolic ring found in the structure of estrogens. The phenol (B) can then scavenge free radicals (C) and resonance-stabilize them (C-D) until reduced (X). Reduction of phenoxy radicals (C) is an enzyme-mediated process that uses ascorbic acid, glutathione-dependent free radical reductase, and a newly discovered NADPH-mediated reductive aromatization. This illustration was loosely based on work of Prokai et al. [79].

Figure 2

Examination of the neuroprotective efficacy of estrogens and analogs. Maximal efficacy, with dose of drug, was examined in a glutamate-induced cytotoxicity model of in vitro retinal ganglion cell death using the retinal ganglion cell-5 cell line. This screening process was used to guide drug selection and design, and to identify highly efficacious compounds for detailed studies of mechanism of action. Abbreviations: 17β-estradiol (E2) is 1,3,5(10)estratriene-3,17 beta-diol; E2Q is 3,5(10)estratriene-3,17 beta-diol-quinol; Estrone (E1) is 3-hydroxyestra-1,3,5(10)-triene-3,17 beta-diol; E1Q is 3-hydroxyestra-1,3,5(10)-triene-3,17 beta-diol-quinol; 17α-estradiol is 1,3,5(10)estratriene-3,17 alpha-diol; 17α-estradiol-quinol is 1,3,5(10)estratriene-3,17 alpha-diol-quinol; ADAEI is 2-adamantyl-3-hydroxyestra-1,3,5(10)-triene-17-one; ADAEIQ is 2-adamantyl-3-hydroxyestra-1,3,5(10)-triene-17-one-quinol; THN is 1,3,6,8-tetrahydroxynapthalene; THNQ is 1,3,6,8-tetrahydroxynapthalene-quinol; ZYC1 is 17β estra-1,3,5(10), 9(11)-tetratriene-3,17-diol; ZYC-3 is 2-(1-adamantyl)-3-hydroxyestra-1,3,5(10)-triene-17-one; ZYC10 is Enantiomer of ZYC1.