Role of nonfeminizing estrogen analogues in neuroprotection of rat retinal ganglion cells against glutamate-induced cytotoxicity
Role of nonfeminizing estrogen analogues in neuroprotection of rat retinal ganglion cells against glutamate-induced cytotoxicity
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DOI：
10.1016/j.freeradbiomed.2004.12.007
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发表时间：
2005-05-01
影响因子：
7.4
通讯作者：
Agarwal, N
中科院分区：
文献类型：
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作者：
Kumar, DM;Perez, E;Agarwal, N
青光眼是一类眼科疾病，其最终导致视力丧失的原因是视网膜神经节细胞的凋亡。尽管青光眼的病因有多种，但氧化应激被认为是神经节细胞死亡的关键机制。从这一角度出发，本文旨在研究17β-雌二醇和三种合成雌激素类似物(ZYC-1、ZYC-3、ZYC-10)作为视网膜神经节细胞神经保护剂的有效性。化合物ZYC-1及其对映体ZYC-10与母体雌激素相比，对雌激素受体的亲和力相似(ZYC-1)或略有降低(ZYC-10)。ZYC-1及其对映体ZYC-10在17β-雌二醇的类固醇C环上含有额外的双键。在ZYC-3中，雌酮A环的C2位增加了金刚烷基，取消了其与雌激素受体的结合。RGC-5细胞(已建立的克隆大鼠视网膜神经节细胞系)和大鼠视网膜主要表达雌激素受体a，并检测到极少量的雌激素受体β。合成的化合物对雌激素受体的亲和力如下：ZYC-3<；ZYC-10<；ZYC-1。采用谷氨酸诱导RGC-5细胞死亡的体外模型。谷氨酸处理导致RGC-5细胞死亡50%-60%，而对照细胞未处理。17β-雌二醇和3个雌激素类似物(0.5~1.0mM)对RGC-5细胞的谷氨酸细胞毒性有保护作用。雌激素类似物的神经保护作用如下：ZYC-3>；ZYC-1>；ZYC-10。抑制TBARS水平的EC50值分别为：ZYC-3和GT；ZYC-10和GT；ZYC-1。此外，这些化合物的作用不依赖雌激素受体，因为包含100 nM ICI 182,780并不能逆转它们对抗谷氨酸攻击的神经保护特性。这些化合物似乎通过独立于经典雌激素受体的途径影响神经保护。这些数据支持这样的假设，即雌激素类似物可能有助于治疗神经退行性疾病，特别是在青光眼等眼病中对视网膜神经节细胞的神经保护。(C)2004 Elsevier Inc.保留所有权利。
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 17 beta-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 17 beta-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 a, 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. 17 beta-Estradiol and the three estrogen analogues (0.5 to 1.0 mu M) 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. EC50 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. (c) 2004 Elsevier Inc. All rights reserved.