Estrogen: Neuroprotection in the Perimenopause

雌激素：围绝经期的神经保护

• 批准号: 7847085
• 负责人: ANNE M ETGEN
• 金额: $ 14.95万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847085
• 关键词: Address; Affect; Age; Aging; American; Animals; Apoptotic; BCL2 gene; Behavioral; Biological; Biology; Brain; Brain Injuries; CA1 neuron loss; Cardiovascular system; Cell Count; Cell Survival; Cessation of life; Cognitive; Cyclic AMP-Responsive DNA-Binding Protein; Diabetes Mellitus; Disease; Down-Regulation; Early treatment; Educational workshop; Estradiol; Estrogens; Female; Future; Growth Factor; Health; Heart Arrest; Hippocampus (Brain); Hormones; Human; Hypothalamic structure; Impaired cognition; Institutes; Insulin-Like Growth Factor I; Ischemia; Knowledge; Menopause; Methods; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Modeling; Nerve Degeneration; Neurologic; Neurons; Nuclear Translocation; Operative Surgical Procedures; Organ; Osteoporosis; Outcome; Ovarian; Ovarian hormone; Ovariectomy; Pathway interactions; Performance; Perimenopause; Physiological; Pituitary Gland; Rattus; Research; Research Personnel; Risk; Risk Factors; Role; Signal Pathway; Site; Somatomedins; Testing; Time; United States National Institutes of Health; Withdrawal; Woman; age related; aging brain; behavior test; caspase-3; cognitive function; critical period; disorder risk; forkhead protein; hippocampal pyramidal neuron; hormone therapy; hypothalamic pituitary ovarian axis; middle age; neuron loss; neuronal survival; neuroprotection; prevent; programs; research study

DESCRIPTION (provided by applicant): Alterations in the hypothalamic-pituitary-ovarian axis in perimenopausal women are associated with multi- organ risk factors for disease, yet the biological mechanisms underlying this increased disease risk are largely unknown. This proposal addresses unanswered questions regarding the vulnerability of the middle- aged brain to global ischemia. In young female rats, the presence of physiological levels of estradiol before and after global ischemia, as might occur during cardiac arrest, reduces hippocampal CA1 neuron loss and associated cognitive impairments. Whether estradiol retains its neuroprotective actions in middle-aged females, and whether the age-related decline in insulin-like growth factor-l (IGF-I) increases vulnerability to ischemia-induced neurodegeneration and cognitive impairment, are unknown. This proposal aims examines the roles of age, estrogen and IGF-I in the survival and function of hippocampal neurons in a rat model of global ischemia. The underlying hypotheses are (1) that the middle-aged brain retains its responsiveness to the neuroprotective actions of estradiol if the duration of estrogen withdrawal is brief ("critical period hypothesis") or circulating levels of IGF-I are maintained, and (2) that estrogen acts in the middle-aged brain to activate specific cell survival pathways and thereby intervenes in apoptotic cascades to prevent death of neurons otherwise "destined to die". Specific Aim 1 uses stereological cell counting and behavioral tests to evaluate the outcome of global ischemia in middle-aged female rats that are intact, ovariectomized at various intervals prior to insult, or ovariectomized and treated with estradiol at various intervals after ovariectomy. If estradiol does not preserve neurons and cognitive function in older hormone-deprived animals, we, will also determine if IGF-I can reinstate estrogen protection. Specific Aim 2 examines the apoptotic death cascades triggered by global ischemia and identifies the site at which estrogen intervenes in these cascades. We will examine 1) mitogen-activated protein kinase and cAMP response element binding protein at early times after ischemia; 2) the anti-apoptotic gene Bcl-2 and activation of caspase 3 at later times after ischemia; 3) inactivation of Akt and subsequent activation of the forkhead transcription factor FKHRL1 at early times after ischemia. These experiments will provide new information on the potential for hormone therapy instituted during the perimenopausal transition to protect the brain from damage due to global ischemia.

描述（由申请人提供）：膜苏联妇女的下丘脑 - 垂体 - 卵巢轴的变化与疾病的多器官风险因素有关，但是这种增加的疾病风险的生物学机制在很大程度上尚不清楚。该提案解决了有关中等大脑对全球缺血的脆弱性的未解决问题。在年轻的雌性大鼠中，全球性缺血之前和之后的生理水平存在（心脏骤停过程中）可能会减少海马CA1神经元丧失和相关的认知障碍。雌二醇是否保留其在中年女性中的神经保护作用，以及与年龄相关的胰岛素样生长因子-L（IGF-I）是否会增加对缺血诱导的神经退行性创世率和认知障碍的脆弱性。该建议的目的是研究年龄，雌激素和IGF-I在全球缺血大鼠模型中海马神经元生存和功能中的作用。 The underlying hypotheses are (1) that the middle-aged brain retains its responsiveness to the neuroprotective actions of estradiol if the duration of estrogen withdrawal is brief ("critical period hypothesis") or circulating levels of IGF-I are maintained, and (2) that estrogen acts in the middle-aged brain to activate specific cell survival pathways and thereby intervenes in apoptotic cascades to prevent death of neurons否则“注定要死”。具体目标1使用立体细胞计数和行为测试来评估中年雌性大鼠全球缺血的结果，这些雌性大鼠完好无损，在侮辱前以各个间隔进行卵巢切除，或在卵巢切除术后各个间隔进行雌二醇治疗。如果雌二醇不保留旧激素剥夺动物的神经元和认知功能，我们还将确定IGF-I是否可以恢复雌激素保护。特定目标2研究了由全球缺血触发的凋亡死亡级联反应，并鉴定出雌激素干预这些级联反应的部位。我们将检查1）缺血后的早期促分裂原激活蛋白激酶和cAMP反应元件结合蛋白； 2）抗凋亡基因Bcl-2和缺血后的后期caspase 3的激活； 3）在缺血后的早期时期，AKT的灭活及随后激活FKHRL1。这些实验将提供有关围绝经内部过渡期间激素治疗潜力的新信息，以保护大脑免受全球性缺血引起的损害。