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The Role of Quinols in Estrogen Neuroprotection

喹啉在雌激素神经保护中的作用

基本信息

批准号：
7012210
负责人：
LASZLO PROKAI
金额：
$ 32.93万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-01-15 至 2007-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7012210
关键词：
Role Quinols Estrogen Neuroprotection

项目摘要

DESCRIPTION (provided by applicant): There has been mounting evidence that estrogens express neuroprotective effects by the suppression of neurotoxic stimuli largely via their direct radical-scavenging activity. The objective of this grant application is to understand this activity by focusing on the underlying chemistry in which the molecular mechanism of the process and the chemical nature and fate of the products derived from the radical-scavenging reaction are considered the key elements. Our hypotheses center on the role of estrogen-derived quinols as specific reaction products whose involvement has been implicated by preliminary data. By systematically varying substituents in the 2- and/or 4-positions of the phenolic A-ring compounds, we should gain insight into the influence of phenoxy-radical (ArO*) stability, electron density of ArO* at the C-1i0 position and, thus, its reactivity towards hydroxyl radical (-0H). The Fenton-reaction, which leads to 0H formation, will be employed as a chemical model. We hypothesize that hydroxylation will be involved upon *0H exposure as an important process that produces non-radical products from estrogens. In the model system that will be used to study the fate of the synthetic estrogens obtained by the systematic modification of the endogenous compounds, only one type of (mono)hydroxylated species, of a quinol structure, is anticipated via a two-step hydroxyl-radical scavenging mechanism. The rate of quinol formation is expected to correlate not only with the steric and electronic elements of the steroidal compounds, but also with their neuroprotective effect. The phenol to quinol pathway may augment the estrogens' free-radical scavenging efficacy, and make a pivotal contribution to neuroprotection. A reductive quinol to phenol transformation (hence, estrogen "recycling") that prevents the depletion of the available neuroprotective estrogens in vivo will also be investigated. This reactivation (in terms of kinetics and influence by the A-ring substituents) will be studied in vitro in cell-free and cellular systems, and by in vivo microdialysis in experimental animals. Support will be sought for the hypothesis that the reduction of quinols is not accompanied by an increased formation of reactive oxygen species. By using glutamate-induced oxidative stress in HT22 cells as an experimental paradigm, we will study the neuroprotective effects of the phenolic A-ring derivatives of estrogens. In addition to structure - activity relationship studies, a correlation between the propensity of the compound to form its quinol product upon -OH exposure and its effective dose in this model system for neuroprotection will be sought. It is anticipated that the new estrogen analogs selected based on mechanistic studies and in vitro screening will show in vivo neuroprotective effects in a transient middle cerebral artery occlusion, a model for cerebral ischemia. Hence, they will serve as new lead compounds for the development of neuroprotective agents with improved efficacy.

描述（由申请人提供）：越来越多的证据表明，雌激素主要通过其直接的自由基清除活性来抑制神经毒性刺激，从而表达神经保护作用。这项拨款申请的目的是通过关注潜在的化学来理解这种活性，其中过程的分子机制和自由基清除反应产生的产物的化学性质和命运被认为是关键因素。我们的假设集中在雌激素衍生的喹啉作为特定反应产物的作用上，其参与已被初步数据所暗示。通过系统地改变酚a环化合物的2位和/或4位取代基，我们应该深入了解苯氧自由基（ArO*）稳定性、ArO*在c - 100位的电子密度以及它对羟基自由基（- 0h）的反应性的影响。生成0H的芬顿反应将被用作化学模型。我们假设羟基化作用将参与*0H暴露作为一个重要的过程，从雌激素产生非自由基产物。在模型系统中，将用于研究内源性化合物系统修饰获得的合成雌激素的命运，只有一种（单）羟基化的物种，喹啉结构，预计通过两步羟基自由基清除机制。喹啉的形成速度不仅与甾体化合物的位阻和电子元素有关，而且与它们的神经保护作用有关。苯酚-喹啉途径可能增强雌激素清除自由基的能力，对神经保护有重要作用。还将研究防止体内可用的神经保护雌激素耗尽的还原性喹啉到苯酚的转化（因此，雌激素“再循环”）。这种再激活（在动力学和a环取代基的影响方面）将在体外无细胞和细胞系统中进行研究，并在实验动物体内进行微透析。将寻求支持这样一种假设，即喹啉的减少并不伴随着活性氧的增加。我们将以谷氨酸诱导的HT22细胞氧化应激为实验范式，研究雌激素酚a环衍生物的神经保护作用。除了构效关系研究外，还将寻求该化合物在- oh暴露后形成其喹啉产物的倾向与其在该神经保护模型系统中的有效剂量之间的相关性。基于机制研究和体外筛选的新型雌激素类似物有望在脑缺血模型大脑中动脉闭塞中显示出体内神经保护作用。因此，它们将作为新的先导化合物，为开发更有效的神经保护药物提供依据。