17β-estradiol and the phytoestrogen genistein attenuate neuronal apoptosis induced by the endoplasmic reticulum calcium-ATPase inhibitor thapsigargin
17β-estradiol and the phytoestrogen genistein attenuate neuronal apoptosis induced by the endoplasmic reticulum calcium-ATPase inhibitor thapsigargin
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DOI：
10.1016/s0039-128x(02)00062-4
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发表时间：
2002-12-01
期刊：
影响因子：
2.7
通讯作者：
Dorsa, DM
中科院分区：
文献类型：
--
作者：
Linford, NJ;Dorsa, DM
雌激素化合物已被证明可以保护神经元免受体外和体内各种有毒刺激的影响，绝经期雌激素的消耗与神经退行性疾病的风险增加有关。染料木素是一种大豆异黄酮衍生物，与雌激素受体结合，具有选择性雌激素受体调节剂（SERM）特性。最近美国食品和药物管理局建议摄入大豆以降低胆固醇，这促使人们对膳食大豆植物化学物质在大脑中潜在的雌激素作用进行了调查。在这项研究中，我们发现50 nM染料木素以雌激素受体依赖的方式显著减少神经元凋亡。大脑中细胞凋亡的重要性已经被认识到，涉及到大脑发育的组织以及对疾病或中风的反应的退化；然而，雌激素化合物对神经元凋亡的影响尚未得到充分的研究。我们利用内质网（ER）钙- atp酶抑制剂thapsigargin建立了初级皮质神经元细胞凋亡毒性模型，以测试17 - β -雌二醇和染料木素的潜在抗凋亡作用。在我们的原代神经元培养中检测到雌激素受体p，但未检测到雌激素受体a。通过线粒体功能丧失、DNA阶梯、核凝聚和断裂以及caspase激活，证实了thapsigargin诱导的细胞凋亡。17 -雌二醇和染料木素均可减少凋亡神经元的数量，并减少含有活性caspase-3的神经元的数量。这种效应被ICI 182780的共加入所阻断。我们的研究结果表明染料木素和17 -雌二醇在初级皮质神经元中具有相似的抗凋亡特性，并且这些特性是通过雌激素受体介导的。(C) 2002年Elsevier Science Inc.出版
Estrogenic compounds have been shown to protect neurons from a variety of toxic stimuli in vitro and in vivo and depletion of estrogen at menopause has been associated with increased risk of neurodegenerative diseases. Genistein is an isoflavone soy derivative that binds to estrogen receptors with selective estrogen receptor modulator (SERM) properties. Recent FDA recommendations of soy intake for cholesterol reduction have prompted investigation into the potentially estrogenic role of dietary soy phytochemicals in the brain. In this study, we have shown that 50 nM genistein significantly reduces neuronal apoptosis in an estrogen receptor-dependent manner. The importance of apoptosis in the brain has been recognized with regard to organization of the developing brain as well as degeneration in response to disease or stroke; however, the effects of estrogenic compounds on neuronal apoptosis have not been thoroughly examined. We developed a model of apoptotic toxicity in primary cortical neurons by using the endoplasmic reticulum (ER) calcium-ATPase inhibitor, thapsigargin, to test potential anti-apoptotic effects of 17beta-estradiol and genistein. Estrogen receptor p, but not estrogen receptor a, was detected in our primary neuron cultures. Thapsigargin-induced apoptosis was confirmed by loss of mitochondrial function, DNA laddering, nuclear condensation and fragmentation, and caspase activation. Both 17beta-estradiol and genistein reduced the number of apoptotic neurons and reduced the number of neurons containing active caspase-3. This effect was blocked by co-addition of ICI 182,780. Our results demonstrate that genistein and 17beta-estradiol have comparable anti-apoptotic properties in primary cortical neurons and that these properties are mediated through estrogen receptors. (C) 2002 Published by Elsevier Science Inc.