Estrogen and the Aging Blood Brain Barrier

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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.