Estrogen and brain vascular inflammation in diabetics

糖尿病患者的雌激素和脑血管炎症

• 批准号: 6899212
• 负责人: DALE Alan PELLIGRINO
• 金额: $ 31.78万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6899212
• 关键词: cell adhesion; cerebral ischemia /hypoxia; diabetes mellitus; estrogens; glycation; hormone therapy; hyperglycemia; image processing; inflammation; intravital microscopy; laboratory rat; leukocytes; neuroprotectants; nuclear factor kappa beta; ovariectomy; progesterone; receptor; receptor expression

DESCRIPTION (provided by applicant): The neuro-and vasculoprotective properties of estrogen have been amply demonstrated in laboratory investigations. However, clinically, there are indications that hormone replacement therapy in women may not be beneficial, and even detrimental. The present project is based upon the concept that clinically-relevant circumstances may occur where estrogen replacement therapy (ERT) is no longer neuroprotective, but neurotoxic. One such circumstance is diabetes/chronic hyperglycemia (CH). Recent results showed that, whereas chronic "physiologic" ERT, in non-diabetic, ovariectomized (OVX) rats protects the brain against ischemic damage, ERT in diabetic OVX females exacerbates the damage. This project is designed to delineate the mechanisms behind this "transformation". The rationale derives from the parallel observations that CH promotes an increase in the levels of advanced glycation end-products (AGEs), while ERT promotes an increased expression of the AGE receptor, RAGE, on cerebrovascular endothelial cells. The resultant increase in RAGE activation unleashes a cascade leading to a sustained increase in the activity of the pro-inflammatory transcriptional regulator, NFkB, and a heightened potential for cerebral inflammatory activity following an ischemic insult. The 4 specific aims of this proposal are guided by the following hypotheses: 1) ERT in diabetic (streptozotocin-treated, chronically [>1 mo] hyperglycemic) OVX females will exacerbate, while ERT in non-diabetics will attenuate post-ischemic (transient forebrain ischemia) cerebrovascular inflammation, as reflected by the extent to which leukocytes adhere to pial venules. 2) Blocking RAGE, its ligands (e.g., AGE), or its downstream effector, NFkB, either via antisense or pharmacologic inhibitor treatments, will prevent the pro-adhesive action of ERT in diabetics. 3) Preventing leukocyte adhesion (via leukopenia), in addition to AGE, RAGE or NFkB blockade, will prevent ERT-associated exacerbation of ischemic brain damage. 4) Chronic progesterone (P) replacement, when combined with ERT, will prevent the pro-inflammatory and neurotoxic actions seen with ERT alone in the diabetic OVX female. Results will be evaluated based upon whether the females are intact, OVX, or OVX + 17B-estradiol (E2)-treated (or E2+P-treated), and whether the rats are diabetic or non-diabetic. The principal variables to be monitored will be post-ischemic (0-10h reperfusion) pial venular adhesion of rhodamine-6G-labeled leukocytes; neuronal cell loss (at 72h reperfusion); and expression of key proteins. The established technique being used for quantitating leukocyte adhesion involves chronic placement of closed cranial windows, intravital microscopy/videometry, and computer-assisted image processing. The results of these studies will permit us to gain an understanding of some of the mechanisms behind estrogen's conversion to the "dark side" and should lead to improvements in the clinical efficacy of hormone replacement treatments.

描述（由申请人提供）：在实验室研究中已经充分证明了雌激素的神经和血管保护特性。但是，从临床上讲，有迹象表明，女性中的激素替代疗法可能没有好处，甚至不利。本项目基于以下概念：雌激素替代疗法（ERT）不再是神经保护剂，而是神经毒性的概念。一种情况是糖尿病/慢性高血糖（CH）。最近的结果表明，尽管慢性“生理” ERT，但在非糖尿病，卵巢切除术（OVX）大鼠中，大脑可保护脑部免受缺血性损害，而糖尿病OVX女性中的ERT则加剧了损害。该项目旨在描述这种“转型”背后的机制。基本原理来自CH的平行观察结果，CH促进了晚期糖基化终产物（年龄）的水平，而ERT则促进了脑血管内皮细胞上年龄受体的表达增加。最终的愤怒激活增加释放了级联反射转录调节剂NFKB活性的级联反应，以及缺血性侮辱后的脑炎症活动的增强潜力。该提案的4个具体目的由以下假设指导：1）糖尿病患者（经链蛋白酶治疗的，长期[> 1 mo]高血糖）OVX女性会加剧，而非糖尿病的ERT会抑制疾病的临时疾病（暂时性的小脑含量），疾病的疾病症状症状疾病症状症状疾病，疾病疾病的特定症状疾病疾病疾病疾病疾病疾病疾病疾病疾病疾病症状。白细胞粘附在猫静脉上。 2）通过反义或药理学抑制剂治疗，阻止愤怒，其配体（例如年龄）或其下游效应子NFKB，将防止ERT在糖尿病患者中的亲粘性作用。 3）防止白细胞粘附（通过白细胞减少）除了年龄，愤怒或NFKB阻滞外，还将防止与ERT相关的缺血性脑损伤加重。 4）慢性孕酮（P）替代与ERT结合使用，将防止单独使用ERT在糖尿病OVX女性中看到的促炎和神经毒性作用。将根据女性是完整的，OVX还是OVX + 17B-雌二醇（E2）处理的（或E2 + P-PREATEADEAD），以及大鼠是糖尿病患者还是非糖尿病患者，对结果进行评估。要监测的主要变量将是若丹明-6g标记的白细胞的缺血后（0-10H再灌注）；神经元细胞损失（72H再灌注）；和关键蛋白的表达。用于定量白细胞粘附的已建立技术涉及封闭的颅窗，插入式显微镜/视频测量法和计算机辅助图像处理的长期放置。这些研究的结果将使我们能够了解雌激素转化为“黑暗面”背后的某些机制，并应提高激素替代治疗的临床疗效。