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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

基本信息

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
项目类别：
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

项目摘要

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，