Estrogen: Neuroprotection in the Perimenopause

描述（由申请方提供）：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相关，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。这项提议解决了关于中年大脑对全脑缺血的脆弱性的未回答的问题。在年轻的雌性大鼠中，生理水平的雌二醇在全脑缺血前后的存在，可能发生在心脏骤停期间，减少海马CA 1神经元损失和相关的认知障碍。雌二醇在中年女性中是否保留其神经保护作用，以及胰岛素样生长因子-I（IGF-I）的年龄相关性下降是否增加缺血诱导的神经变性和认知障碍的脆弱性，目前尚不清楚。本研究旨在探讨年龄、雌激素和IGF-I在大鼠全脑缺血模型海马神经元存活和功能中的作用。基本的假设是：（1）如果雌激素停药的时间很短，中年人的大脑对雌二醇的神经保护作用仍有反应（“关键期假说”）或IGF-I的循环水平得以维持，和（2）雌激素在中年大脑中起作用以激活特定的细胞存活途径，从而干预凋亡级联反应以防止神经元死亡。注定要死的人”。具体目标1使用体视学细胞计数和行为测试来评估中年雌性大鼠的全脑缺血的结果，所述中年雌性大鼠是完整的、在损伤之前以不同间隔切除卵巢的，或在卵巢切除后以不同间隔切除卵巢并用雌二醇治疗的。如果雌激素不能保护老年雌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。特异性目的2检查了由全脑缺血引发的凋亡性死亡级联反应，并确定了雌激素干预这些级联反应的部位。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）缺血后后期的抗凋亡基因Bcl-2和caspase 3的激活; 3）缺血后早期Akt的失活和随后的叉头转录因子FKHRL 1的激活。这些实验将提供新的信息，在围绝经期过渡期间制定的激素治疗的潜力，以保护大脑免受损害，由于全球缺血。

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.