Estrogen: Neuroprotection in the Perimenopause

描述(申请人提供)：围绝经期妇女下丘脑-垂体-卵巢轴的改变与疾病的多器官风险因素有关，但这种疾病风险增加的生物学机制在很大程度上尚不清楚。这项建议解决了有关中年大脑对全球缺血的脆弱性的未回答问题。在年轻的雌性大鼠中，在全脑缺血前后存在生理水平的雌二醇，就像在心脏骤停期间可能发生的那样，减少了海马CA1神经元的损失和相关的认知损伤。雌激素在中年女性中是否保持其神经保护作用，以及胰岛素样生长因子-L(IGFI)的年龄相关性下降是否会增加缺血诱导的神经变性和认知障碍的易感性，目前尚不清楚。本研究旨在研究AGE、雌激素和IGF-I在全脑缺血大鼠海马神经元存活和功能中的作用。潜在的假说是(1)如果雌激素撤除的持续时间很短(“关键期假说”)或IGF-I的循环水平保持不变，则中年大脑保持对雌二醇的神经保护作用的反应性，以及(2)雌激素在中年大脑中作用于激活特定的细胞生存途径，从而干预细胞凋亡级联反应，以防止否则“注定死亡”的神经元死亡。特异靶1采用体视学细胞计数和行为学测试方法，对成年雌性大鼠全脑缺血的转归进行评估，包括正常成年雌性大鼠、去卵巢前不同时间段摘除卵巢、去卵巢后不同时间段去卵巢加雌激素治疗。如果雌激素不能保护缺乏激素的老年动物的神经元和认知功能，我们也将确定IGF-I是否可以恢复雌激素保护。特殊目的2检查由全球缺血引发的细胞凋亡级联反应，并确定雌激素在这些级联反应中的干预部位。我们将检测1)缺血后早期的丝裂原活化蛋白激酶和cAMP反应元件结合蛋白；2)缺血后后期抗凋亡基因Bcl-2和caspase 3的激活；3)Akt的失活和随后在缺血后早期叉头转录因子FKHRL1的激活。这些实验将提供有关在围绝经期过渡期间实施激素治疗以保护大脑免受全球缺血损伤的可能性的新信息。

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.