Estrogen and the Aging Blood Brain Barrier

本研究旨在探讨女性生殖老化对健康的影响。完整的血屏障（BBB）对维持大脑的内稳态至关重要。随着年龄的增长，即使血脑屏障的基线渗透性可能不会改变，也有报道称它可能变得更容易受到病理生理损伤，并且很容易被破坏。尽管绝经后雌激素替代疗法对中风的益处尚未在临床上确定，但在大多数实验动物研究中，使用雌激素治疗大脑中动脉（MCA）闭塞后，梗死的大小和神经功能缺损显著减少。雌激素的神经保护机制可能来源于血管和/或非血管。我们的初步数据表明雌激素可能保护血脑屏障。脑缺血时，血脑屏障破坏是导致血管源性水肿和继发性脑损伤的重要事件。我们假设如下：雌激素的神经保护机制之一可能是通过减轻局灶性脑缺血引起的血脑屏障破坏程度。2. 当血脑屏障受损时，老年人的破坏程度可能比年轻人更严重。3. 雌激素预处理可降低衰老脑血脑屏障的破坏程度。这些假设将在切除卵巢的幼龄（4-5个月）、老年（22-24个月）和高龄（30-32个月）雌性大鼠中进行研究。血脑屏障会被MCA结扎破坏。大鼠将长期接受低剂量和高剂量的雌激素治疗。由于雌激素可能改变血脑屏障本身和/或灌注毛细血管表面积，因此本提案将确定小分子和大分子的传递系数、灌注毛细血管表面积和通透性。将进行定量组织分析，以确定雌激素对血脑屏障破坏时脑毛细血管分布和通透性变化的影响。我们还将研究雌激素和兴奋性氨基酸是否在血脑屏障保护中相互作用。这些研究将回答雌激素是否保护衰老大脑中的血脑屏障。本研究将为进一步研究衰老脑血脑屏障形成奠定基础，以确定雌激素保护血脑屏障的机制，以及雌激素对受体、信息和蛋白质水平的影响及其随年龄的变化。我们认为这部分与减少兴奋性毒性有关。我们的研究结果将对雌激素治疗脑卒中的临床应用以及了解年龄相关脑血管变化的病理生理学具有重要意义。

The purpose of this project is to investigate the health related consequences of female reproductive aging. An intact blood-barrier (BBB) is essential in maintaining the homeostasis of the brain. With aging, even through the baseline permeability of the BBB may not change, there are reports that it could become more vulnerable to pathophysiological insults and could easily be disrupted. Even though the benefit of postmenopausal estrogen replacement therapy for stroke is not yet established clinically, in most studies using laboratory animals, the size of infarction and the neurological deficit are significantly reduced after middle cerebral artery (MCA) occlusion when treated with estrogen. The mechanism of neuroprotection by estrogen could be of vascular and/or non-vascular origin. Our preliminary data suggest that estrogen may protect the BBB. During cerebral ischemia, BBB disruption is a critical event leading to vasogenic edema and secondary brain injury. We hypothesize the following: 1. One of the mechanisms of neuroprotection by estrogen would be through attenuating the degree of BBB disruption caused by focal cerebral ischemia. 2. When the BBB is damaged, the degree of disruption could be greater in the senescent than in the young brain. 3. Pretreatment with estrogen would decrease the degree of the BBB disruption in the senescent brain. These hypotheses will be studied in ovariectomized young (4-5 months) and old (22-24 months) and very old (30-32 months) female rats. The BBB will be disrupted by MCA ligation. Rats will be chronically treated with low and high doses of estrogen. Since estrogen may alter the BBB itself and/or perfused capillary surface area, the transfer coefficient, perfused capillary surface area, and permeability for both small and large molecules will be determined in this proposal. Quantitative tissue analysis to determine the effects of estrogen on distribution on distribution and changes in the permeability of cerebral capillaries during BBB disruption will be performed. We will also examine whether the interaction between estrogen and excitatory amino acids in BBB protection. These studies will answer whether estrogen protects BBB in the senescent brain. This study will form the basis of future studies on the BBB of the senescent brain in order to determine the mechanism by which estrogen protects the BBB and the effects of estrogen on receptors, messages, and protein levels, and their changes with aging. We thing this is related, in part, to reduced excitotoxicity. The information obtained from our study will be crucially important for the clinical application of estrogen therapy for stroke as well as understanding the pathophysiology of age related cerebrovascular changes.