Estradiol treatment of stress-related psychiatric disorders in Veterans

雌二醇治疗退伍军人压力相关精神疾病

• 批准号: 10484783
• 负责人: Todd D Gould
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10484783
• 关键词: Affect; Age; Amygdaloid structure; Animal Model; Animals; Antidepressive Agents; Anxiety; Aromatase; Basic Science; Behavior; Behavioral; Biological Availability; Biological Markers; Brain; Caring; Data; Development; Disease; Disease model; Effectiveness; Erectile dysfunction; Estradiol; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Exhibits; Exposure to; Extinction; Female; Fright; Funding; Future; Galanin; Goals; Gynecomastia; Hormones; Human; Hypogonadism; Individual; Investigational Drugs; Knowledge; Measures; Mediating; Mediator; Mental Depression; Mental disorders; Military Personnel; Modeling; Mus; NADP; Nucleus Accumbens; Oral; Oral Administration; Oxidoreductase; Pathologic; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology and Toxicology; Phenotype; Pituitary Gland; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Predisposition; Prodrugs; Production; Progesterone Receptors; Property; Rattus; Risk Factors; Rodent; Rodent Model; Role; Signal Transduction; Startle Reaction; Stress; Structure; Testing; Testosterone; Therapeutic; Translating; Treatment Effectiveness; Treatment Efficacy; Uterus; Veterans; Woman; acute stress; age related; aged; biological adaptation to stress; depressive symptoms; deprivation; experimental study; human male; improved; in vivo evaluation; intravenous administration; maladaptive behavior; male; men; mental development; military veteran; neural circuit; neuropsychiatric disorder; neuropsychiatry; novel; novel therapeutics; pharmacologic; pre-clinical; receptor expression; response; sex; side effect; stress related disorder; stress resilience; stressor; testosterone replacement therapy

Stress is a major risk factor for the development of various neuropsychiatric conditions, including depression, anxiety, and post-traumatic stress disorder (PTSD), which disproportionately affect our military personnel and Veterans. We have discovered that brain conversion of 17β-estradiol (E2) from circulating testosterone promotes a maladaptive response to stress in male mice. We have found that the absence of E2 in brain, but not testosterone per se, underlies this susceptibility. Our preliminary data provides evidence for the effectiveness of E2 as a novel antidepressant and have established a circuit-based mechanism through which stress interacts with hypogonadism to mediate depressive-like behavior in males. We hope to translate these basic scientific discoveries into tangible benefits for military personnel and Veterans of both sexes who urgently need improved care for stress-related disorders. While E2 is not a viable treatment in human male populations due to its peripheral side effects, the E2 bioprecursor 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) overcomes this limitation by delivering E2 directly to the brain after conversion by NADPH-dependent reductase. Unfortunately, DHED has poor oral bioavailability, which limits its potential use as a novel therapeutic in patients. We propose to advance knowledge regarding the role of targeting E2 signaling as a treatment mechanism for stress-induced neuropsychiatric disorders, and further the discovery of a brain-selective and orally bioavailable prodrug of DHED based on the previously characterized structure of the molecule. In Specific Aim #1, we will use rodent models of psychiatric disease treatment effectiveness to further determine the role of E2 signaling in mediating stress susceptibility in males. These studies will address hypogonadism- and age-dependent mechanisms of enhanced susceptibility to stress and pathological fear, relevant to neuropsychiatric conditions that disproportionately affect those who have served in the military. This will help identify which psychiatric disorders, in addition to depression, may be most amenable to E2-mediated treatment. In Specific Aim #2, we will assess candidate prodrugs for improved oral bioavailability. We will determine the oral bioavailability of DHED prodrugs by comparing levels of DHED and E2 in the brain following intravenous and oral administration in male and female rodents. Those prodrugs that exhibit favorable oral bioavailability and E2 production in the brain will be tested for in vivo response to E2-related biomarkers and therapeutic efficacy for stress-related phenotypes. At completion of our experiments, we will have an improved understanding of the role of estrogen signaling in depression, PTSD, and other stress-influenced neuropsychiatric conditions in males and have better defined a novel treatment approach for both males and females with estrogen responsive disorders. Additionally, we will generate preclinical data that will support a future treatment for military personnel and Veterans suffering from stress-induced neuropsychiatric conditions.

压力是各种神经精神疾病发展的主要风险因素，包括抑郁症， 焦虑和创伤后应激障碍(PTSD)，这对我们的军事人员和 退伍军人。我们发现，脑部从循环中的睾酮转化为17β-雌二醇(E_2)可促进 雄性小鼠对压力的不适应反应。我们已经发现，大脑中缺乏E2，但不是 睾丸激素本身就是这种易感性的基础。我们的初步数据提供了证据证明了 E2作为一种新的抗抑郁药物，并建立了一种基于电路的机制，通过这种机制，应激可以相互作用 性腺功能减退来调节男性的抑郁样行为。我们希望将这些基本的科学知识转化为 为迫切需要改进的军事人员和退伍军人带来实实在在的好处 关注与压力相关的疾病。虽然E2在人类男性人群中不是一种可行的治疗方法，但由于其 外周副作用，E2生物递归药物10β，17β-二羟基-1，4-二烯-3-酮(DHED)克服了这一点 限制通过NADPH依赖的还原酶转化后将E2直接输送到大脑中。不幸的是， DHED的口服生物利用度较低，这限制了其作为一种新的治疗方法在患者中的潜在用途。我们建议 促进对靶向E2信号作为应激诱导的治疗机制的作用的认识 神经精神障碍，以及进一步发现脑选择性和口服生物利用度的DHED前药 基于先前表征的分子结构。 在具体目标#1中，我们将使用啮齿动物模型进一步确定精神疾病的治疗效果 E2信号在调节男性应激易感性中的作用。这些研究将解决性腺功能减退症- 和年龄相关的增强对压力和病理性恐惧的易感性的机制，与 神经精神疾病对那些曾在军队服役的人造成不成比例的影响。这会有帮助的 确定除了抑郁症之外，哪些精神疾病最容易接受雌激素2介导的治疗。 在具体目标2中，我们将评估改善口服生物利用度的候选前药。我们将确定 比较静脉注射DHed和E_2后DHed前药的口服生物利用度 雄性和雌性啮齿动物经口给药。那些表现出良好的口服生物利用度和 将测试大脑中产生的E2对E2相关生物标志物的体内反应和治疗效果 与压力相关的表型。 在我们的实验完成后，我们将对雌激素信号在 抑郁症、创伤后应激障碍和其他受压力影响的男性神经精神疾病，并更好地定义了 男性和女性雌激素反应性障碍的新治疗方法。此外，我们还将 生成临床前数据，支持军事人员和退伍军人遭受 应激诱发的神经精神疾病。