The Role of 17β-Estradiol in Delirium

摘要 精神错乱通常是由尿路感染(UTI)引起的，这种情况 对老年妇女的影响不成比例，并导致死亡率增加，持续时间延长 并加速了长期认知能力的下降。神志不清的现有治疗方法 主要是对诱发原因的处理，对环境贡献者的修改，以及 避免服用致幻药物；然而，并不涉及潜在的病理生物学 这种情况。 我们开发了一种新的尿路感染诱导的精神错乱的小鼠模型，并产生了令人信服的 初步数据显示，外源性给予17β-雌二醇在 减轻尿毒症引起的精神错乱。这些发现可能至少部分解释了为什么老年女性， 更年期后17β-雌二醇水平降低的人，特别容易患上 发展中的精神错乱。 在R21的应用中，我们建议使用我们的新的尿路感染小鼠模型- 诱导的精神错乱，去卵巢的小鼠，最先进的行为测试，以及遗传学 改良小鼠以确定17β-雌二醇是否改善结构和功能 通过G蛋白偶联雌激素受体引起的精神错乱表型1.鉴于缺乏 对精神错乱的循证药物治疗，这项研究的发现可能 具有广泛的临床意义，包括提供新的临床前理由 使用现有药物17β-雌二醇的短期应用来改善尿路感染的临床试验 世界各地数百万老年妇女的诱发性精神错乱和生活质量。

ABSTRACT Delirium is frequently precipitated by urinary tract infection (UTI), a condition that disproportionately affects older women and contributes to increased mortality, prolonged length of stay, and accelerated long-term cognitive decline. Existing treatments for delirium center largely on treatment of the precipitating cause, modification of environmental contributors, and avoidance of deliriogenic medications; however, do not address the underlying pathobiology of the condition. We have developed a novel mouse model of UTI-induced delirium and generated compelling preliminary data that demonstrate a potential role for exogenously administered 17β-estradiol in mitigating UTI-induced delirium. These findings may explain, at least in part, why older women, who after menopause have reduced levels of 17β-estradiol, are particularly susceptible to developing delirium. In this R21 application, we propose to use our novel mouse model of urinary tract infection- induced delirium, oophorectomized mice, state-of-the-art behavioral testing, and genetically modified mice to determine whether 17β-estradiol ameliorates the structural and functional phenotypes of delirium via the G protein-coupled estrogen receptor 1. Given the lack of evidence-based pharmacological treatments for delirium, the findings from this research could have widespread clinical implications, including providing novel pre-clinical justification for clinical trials using a short-term application of an existing drug, 17β-estradiol, to ameliorate UTI- induced delirium and quality of life for millions of older women around the world.