The Role of Quinols in Estrogen Neuroprotection

喹啉在雌激素神经保护中的作用

• 批准号: 6831665
• 负责人: LASZLO PROKAI
• 金额: $ 17.45万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-15 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6831665
• 关键词: Role; Quinols; Estrogen; Neuroprotection

EXCEEDTHE SPACE PROVIDED. 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-10 position and, thus, its reactivity towards hydroxyl radical (*OH). The Fenton-reaction, which leads to *OH formation, will be employed as a chemical model. We hypothesize that hydroxylation will be involved upon *OH 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 system, and by in vivo microdialysis in experimental animals. Support will be sought to 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. PERFORMANCE SITE ========================================Section End===========================================

超过提供的空间。 有越来越多的证据表明，雌激素在很大程度上通过其直接自由基扫描活性抑制神经毒性刺激来表达神经保护作用。该赠款应用的目的是通过关注基础化学方法来理解这项活动，在这种化学中，该过程的分子机制以及从自由基消除反应中得出的产物的化学性质和命运被认为是关键要素。我们的假设集中在雌激素衍生的喹诺尔作为特定反应产物的作用，其参与已与初步数据有关。通过在酚类A型圈化合物的2和/或4位中系统地变化的取代基，我们应该深入了解苯氧基 - 自由基（ARO*）稳定性的影响，ARO的电子密度“在C-10位置处”，因此，它对羟基自由基（*oh）的反应性均为fentson-reaction。假设在 *OH暴露时将涉及羟基化，这是一个重要的过程，该过程可从模型系统中产生非自由基产物。清除机制。 “回收”可以防止在体内耗尽可用的神经保护性雌激素，还将研究这种重新激活（根据A形替代物的动力学和影响），将在无细胞和细胞系统中进行体外研究，并通过体内的微观效力。通过使用谷氨酸诱导的HT22细胞中的氧化应激的形成增加，我们将研究酚类酚元衍生物的神经保护作用，除雌激素的酚类衍生物与结构关系中的相关性以及该模型的相关性。遇到的。预计基于机械研究和体外筛查的新雌激素类似物将在瞬时脑部动脉闭塞中显示出体内神经保护作用，这是一种用于脑部局部的大脑局部==============================================================================================================