Estrogen: Neuroprotection in the Perimenopause

描述（由申请人提供）：围绝经期妇女下丘脑-垂体-卵巢轴的改变与疾病的多器官危险因素有关，但这种疾病风险增加的生物学机制在很大程度上是未知的。这一建议解决悬而未决的问题，关于脆弱性的中年大脑对全球缺血。在年轻雌性大鼠中，全身缺血前后存在生理水平的雌二醇（可能发生在心脏骤停期间），可减少海马CA1神经元丢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）的下降是否会增加缺血性神经变性和认知障碍的易感性，这些都是未知的。本研究旨在探讨年龄、雌激素和igf - 1在大鼠全脑缺血海马神经元存活和功能中的作用。潜在的假设是：(1)如果雌激素停药时间短（“关键时期假设”）或维持IGF-I循环水平，中年大脑保留其对雌二醇神经保护作用的反应性；(2)雌激素在中年大脑中激活特定的细胞生存途径，从而干预凋亡级联，以防止否则“注定死亡”的神经元死亡。特异性目的1使用体视细胞计数和行为学测试来评估损伤前不同时间间隔切除卵巢的完整中年雌性大鼠，或卵巢切除后不同时间间隔用雌二醇治疗的雌性大鼠的全脑缺血结果。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，我们也将确定igf - 1是否可以恢复雌激素的保护。特异性目的2检查由全局缺血引发的凋亡死亡级联反应，并确定雌激素在这些级联反应中的干预位置。我们将在缺血后早期检测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及caspase 3的活化；3)缺血后早期Akt失活，随后叉头转录因子FKHRL1激活。这些实验将提供新的信息，在围绝经期过渡期间制定激素治疗的潜力，以保护大脑免受全脑缺血造成的损害。

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.