Estrogen and the Aging Blood Brain Barrier

本项目的目的是调查女性生殖老龄化对健康的影响。一个完整的血屏障(BBB)对于维持大脑的内稳态是必不可少的。随着年龄的增长，即使血脑屏障的基线通透性可能不会改变，但有报道称，它可能会变得更容易受到病理生理的侮辱，并且很容易被破坏。尽管绝经后雌激素替代治疗中风的益处尚未在临床上得到证实，但在大多数使用实验室动物的研究中，使用雌激素治疗大脑中动脉(MCA)闭塞后，脑梗塞的范围和神经功能障碍显著减少。雌激素的神经保护机制可能是血管和/或非血管来源的。我们的初步数据表明，雌激素可以保护血脑屏障。在脑缺血过程中，血脑屏障破坏是导致血管源性水肿和继发性脑损伤的关键事件。我们的假设如下：1.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来实现的。2.当血脑屏障受损时，衰老大脑的破坏程度可能比年轻大脑更严重。3.雌激素可减轻衰老大鼠脑内血脑屏障的破坏程度。这些假说将在去卵巢的年轻(4-5月龄)、老年(22-24月龄)和高龄(30-32月龄)雌性大鼠身上进行研究。血脑屏障将被大脑中动脉结扎所破坏。大鼠将接受低剂量和高剂量雌激素的慢性治疗。由于雌激素可以改变血脑屏障本身和/或灌流的毛细血管表面积，因此传递系数、灌流的毛细血管表面积以及小分子和大分子的通透性将在本方案中确定。将进行定量组织分析，以确定雌激素对分布的影响，在血脑屏障破坏期间，大脑毛细血管的分布和通透性的变化。我们还将研究雌激素和兴奋性氨基酸之间的相互作用是否对血脑屏障具有保护作用。这些研究将回答雌激素是否能保护衰老大脑中的血脑屏障。这项研究将为今后对衰老脑血脑屏障的研究奠定基础，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，以及它们随年龄的变化。我们认为，这在一定程度上与兴奋性毒性的降低有关。本研究获得的信息将对雌激素治疗中风的临床应用以及了解年龄相关性脑血管变化的病理生理学具有至关重要的意义。

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.