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.