Development of 17α-estradiol as a neuroprotective therapeutic agent -: Rationale and results from a phase I clinical study
Development of 17α-estradiol as a neuroprotective therapeutic agent -: Rationale and results from a phase I clinical study
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DOI：
10.1196/annals.1347.008
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发表时间：
2005-01-01
期刊：
影响因子：
--
通讯作者：
Howell, N
中科院分区：
文献类型：
--
作者：
Dykens, JA;Moos, WH;Howell, N
17α - 雌二醇（17α - E2）与其异构体，即强效女性化激素17β - 雌二醇（17β - E2）仅在一个碳原子的立体化学结构上有所不同，但这足以使其作为一种反式激活激素的活性至少降低200倍。尽管其激素活性微弱，但17α - E2在保护多种细胞类型（包括原代神经元）免受多种致命且与病因相关的应激源（包括淀粉样蛋白毒性、血清剥夺、氧化应激、兴奋性毒性和线粒体抑制等）方面，与17β - E2具有同等效力。此外，两种雌二醇异构体在中风、阿尔茨海默病（AD）和帕金森病（PD）的动物模型中均显示出疗效。许多实验室的数据产生了一种机制模型，其中17α - E2嵌入细胞膜，在那里它终止脂质过氧化链式反应，从而保持膜的完整性，并且它又通过谷胱甘肽或NADPH经酶促偶联进行氧化还原循环。保持膜的完整性对线粒体功能至关重要，内膜通透性的丧失会启动坏死和凋亡途径。因此，通过作为一种线粒体保护剂，17α - E2可阻止细胞死亡，并相应地在一系列退行性疾病（包括AD、PD、弗里德赖希共济失调和肌萎缩侧索硬化症）中提供治疗益处，同时避免了具有更强激素活性的类似物所引发的常见不良反应。本文介绍了口服17α - E2（硫酸钠盐结合物）的I期临床研究成功所获得的积极安全性和药代动力学数据，并讨论了其未来临床评估的几种选择。
17 alpha-estradiol (17 alpha-E2) differs from its isomer, the potent feminizing hormone 17 beta-estradiol (17 beta-E2), only in the stereochemistry at one carbon, but this is sufficient to render it at least 200-fold less active as a transactivating hormone. Despite its meager hormonal activity, 17 alpha-E2 is as potent as 17 beta-E2 in protecting a wide variety of cell types, including primary neurons, from a diverse array of lethal and etiologically relevant stressors, including amyloid toxicity, serum withdrawal, oxidative stress, excitotoxicity, and mitochondrial inhibition, among others. Moreover, both estradiol isomers have shown efficacy in animal models of stroke, Alzheimer's disease (AD), and Parkinson's disease (PD). Data from many labs have yielded a mechanistic model in which 17 alpha-E2 intercalates into cell membranes, where it terminates lipid peroxidation chain reactions, thereby preserving membrane integrity, and where it in turn is redox cycled by glutathione or by NADPH through enzymatic coupling. Maintaining membrane integrity is critical to mitochondrial function, where loss of impermeability of the inner membrane initiates both necrotic and apoptotic pathways. Thus, by serving as a mitoprotectant, 17 alpha-E2 forestalls cell death and could correspondingly provide therapeutic benefit in a host of degenerative diseases, including AD, PD, Friedreich's ataxia, and amyotrophic lateral sclerosis, while at the same time circumventing the common adverse effects elicited by more hormonally active analogues. Positive safety and pharmacokinetic data from a successful phase I clinical study with oral 17 alpha-E2 (sodium sulfate conjugate) are presented here, and several options for its future clinical assessment are discussed.