Glaucoma is a family of
eye disorders whose ultimate cause of vision loss is apoptosis of retinal ganglion cells. Although several etiologies of
glaucoma exist, oxidative stress is thought to be a key mechanism by which
ganglion cells die. From this perspective, the work presented here was designed to examine the efficacy of 17beta-estradiol and three
synthetic estrogen analogues (ZYC-1, ZYC-3, ZYC-10) as retinal ganglion cell
neuroprotectants. Compound ZYC-1 and its enantiomer ZYC-10, containing an additional double bond in the
steroid C ring of 17beta-estradiol, had similar (ZYC-1) or modestly reduced (ZYC-10) affinity for
estrogen receptors compared to the parent
estrogen. In the case of ZYC-3, the addition of an adamantyl group to the C2 position of the A ring of
estrone abolished its binding to the
estrogen receptors. RGC-5 cells (an established clonal rat retinal ganglion cell line) and rat retinas were shown to predominantly express
estrogen receptor alpha, with minimal detectable levels of
estrogen receptor beta. The affinity of the synthetic compounds for
estrogen receptors was as follows: ZYC-3 < ZYC-10 < ZYC-1. An in vitro model of
glutamate-induced RGC-5 cell death was used.
Glutamate treatment resulted in 50-60% RGC-5 cell death with respect to control untreated cells. 17beta-estradiol and the three
estrogen analogues (0.5 to 1.0 microM) protected the RGC-5 cells against
glutamate cytotoxicity. The efficacy of neuroprotection by the
estrogen analogues was as follows: ZYC-3 > ZYC-1 > ZYC-10. EC(50) values for inhibition of
TBARS levels were as follows: ZYC-3 > ZYC-10 > ZYC-1. Furthermore, these compounds worked independent of
estrogen receptors, as inclusion of 100 nM
ICI 182,780 did not reverse their neuroprotective properties against
glutamate insult. These compounds seem to affect neuroprotection via pathways independent of the classical
estrogen receptors. The data support the hypothesis that
estrogen analogues may be useful in the treatment of
neurodegenerative diseases, particularly in neuroprotection of retinal ganglion cells in ocular pathologies such as
glaucoma.