Estrogen: Neuroprotection in the Perimenopause

雌激素：围绝经期的神经保护

• 批准号: 7068153
• 负责人: ANNE M ETGEN
• 金额: $ 34万
• 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/7068153
• 关键词: BCL2 gene /protein; age difference; aging; apoptosis; behavior test; cAMP response element binding protein; cell sorting; cerebral ischemia /hypoxia; cysteine endopeptidases; estradiol; gene induction /repression; hippocampus; hormone regulation /control mechanism; insulinlike growth factor; laboratory rat; mature animal; mitogen activated protein kinase; neural degeneration; neuropathology; neuroprotectants; ovariectomy; protein localization; tissue /cell culture; transcription factor

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）：围绝经期女性下丘脑-垂体-卵巢轴的改变与疾病的多器官危险因素相关，但这种疾病风险增加背后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年大脑对整体缺血的脆弱性的尚未解答的问题。在年轻雌性大鼠中，在心脏骤停期间可能发生的全身缺血前后，雌二醇生理水平的存在可减少海马 CA1 神经元损失和相关的认知障碍。雌二醇是否在中年女性中保留其神经保护作用，以及与年龄相关的胰岛素样生长因子-1 (IGF-I) 下降是否会增加缺血引起的神经退行性变和认知障碍的脆弱性，目前尚不清楚。该提案旨在研究年龄、雌激素和 IGF-I 在大鼠全身缺血模型中海马神经元的存活和功能中的作用。潜在的假设是 (1) 如果雌激素戒断持续时间很短（“关键期假说”）或维持 IGF-I 的循环水平，中年大脑仍保留对雌二醇神经保护作用的反应性，以及（2 ）雌激素在中年大脑中起作用，激活特定的细胞生存途径，从而干预细胞凋亡级联，以防止神经元死亡，否则“注定会死亡”。具体目标 1 使用体视细胞计数和行为测试来评估中年雌性大鼠的整体缺血结果，这些雌性大鼠完好无损，在损伤前以不同时间间隔切除卵巢，或在卵巢切除后以不同时间间隔切除卵巢并用雌二醇治疗。如果雌二醇不能保护老年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。具体目标 2 检查由整体缺血引发的细胞凋亡级联反应，并确定雌激素干预这些级联反应的位点。我们将在缺血后的早期检查 1) 丝裂原激活蛋白激酶和 cAMP 反应元件结合蛋白； 2) 缺血后抗凋亡基因Bcl-2和caspase 3的激活； 3) 缺血后早期 Akt 失活并随后激活叉头转录因子 FKHRL1。这些实验将提供关于围绝经期过渡期间激素疗法的潜力的新信息，以保护大脑免受整体缺血造成的损害。