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Endocrinology Vol. 145, No. 12 5471-5475
Copyright © 2004 by The Endocrine Society

BRIEF COMMUNICATION

17ß-Estradiol Differentially Regulates Blood-Brain Barrier Permeability in Young and Aging Female Rats

Shameena Bake and Farida Sohrabji

Department of Human Anatomy and Medical Neurobiology, Texas A&M University Health Science Center College of Medicine, College Station, Texas 77843-1114

Address all correspondence and requests for reprints to: Farida Sohrabji, 228 Reynolds Medical Building, Texas A&M University Health Science Center College of Medicine, College Station, Texas 77843-1114. E-mail: f-sohrabji{at}tamu.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Because both brain and its vasculature are potent targets of estrogen, age-related decline in estrogen levels or alterations in estrogen receptors may disrupt the integrity of the blood-brain barrier, leading to increased influx of toxic products. The present study tested the hypothesis that the blood-brain barrier is more permeable in reproductive senescent animals and will respond differently to estrogen replacement as compared with young adult females. Young adult and reproductive senescent rats were ovariectomized and replaced with an estrogen or control pellet. We found a 2- to 4-fold increase in extravasation of dye in the olfactory bulb and hippocampus of reproductive senescent females compared with young adults. Furthermore, estrogen significantly reduced dye extravasation in both olfactory bulb and hippocampus in young adults compared with age-matched counterparts that received a control pellet. However, estrogen replacement increased dye extravasation in the hippocampus of reproductive senescent females compared with age-matched control-pellet replaced animals, whereas dye extravasation was unchanged by estrogen in the olfactory bulb of senescent females. There were no age- and estrogen-related differences in dye accumulation in the pituitary gland, which is a circumventricular organ. These results support the hypothesis that the hormonal decline that marks reproductive senescence leads to increased permeability of the blood-brain barrier, which is further exacerbated by estrogen treatment in specific regions.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE BLOOD-BRAIN BARRIER is essential to the maintenance of homeostasis of the central nervous system microenvironment, which is crucial for normal neural function. This barrier, which consists of a system of specialized semiimpermeable capillary structures, has evolved to exclude toxic substances from entering the brain. A monolayer of endothelial cells forms the capillary bed and serves as a mechanical barrier. These specialized endothelial cells differ from endothelial cells of other regions by the presence of distinct structures such as tight junctions, absence of fenestrae, and very few pinocytic vesicles (1).

Transcellular passage of hydrophilic molecules across the blood-brain barrier is tightly regulated by endothelial cells via reduced pinocytosis, whereas paracellular transport is inhibited by tight junctions between adjacent cells (2). Other mechanisms of transport across the blood-brain barrier include endocytosis through specific receptors (e.g. insulin and transferrin), absorptive endocytosis and transcytosis (3, 4). Age-related changes in cerebral vasculature are accompanied by increased permeability, thus exposing the brain to a higher influx of toxins (5). In females, reproductive (endocrine) senescence, accompanied by disruptions of gonadal hormone production, is a critical physiological aging event and it is currently not known how this event affects the blood-brain barrier.

Besides its well-known reproductive roles, estrogen replacement is also neuroprotective after brain injury. Estrogens decrease infarct size after occlusion of forebrain vessels (6, 7) and attenuate loss of cholinergic function and growth factors after excitotoxic or mechanical injury (8, 9). However, our recent studies indicate that estrogen replacement is neuroprotective only in certain age groups of rats. Interestingly, estrogen increases availability of trophic molecules such as brain-derived neurotrophic factor in the forebrain of estrogen-replaced ovariectomized young adult rats (10), whereas in older or reproductive senescent animals estrogen elicits an opposite effect (11). More recent studies revealed that basal and lesion-induced inflammatory cytokines are elevated in the forebrain of aging animals (12), which, in turn, places the aging brain at high risk for neurodegenerative diseases.

Because both brain and vascular system are potent targets of estrogen, age-related changes in hormone levels may have profound deleterious influence on the integrity of blood-brain barrier, thereby leading to increased influx of blood-borne pathogens and other cytotoxic products to the brain. Common cardiovascular diseases such as hypertension, ischemia, and stroke all adversely affect the integrity of the blood-brain barrier (13, 14) and recent research clearly indicates a critical role of blood-brain barrier in progressive central nervous system disorders (15). Although the role of estrogen in maintaining the integrity of the blood-brain barrier has received some attention, the correlation between barrier dysfunction and changes associated with reproductive status remains unclear. Using dye transfer as an indicator of permeability, the present study tested the hypothesis that the integrity of blood-brain barrier changes with reproductive age of an animal and that estrogen differentially regulates transfer across the barrier.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
All Sprague Dawley rats were purchased as young adults females (4 months, average weight 225–250 g; Harlan Laboratories, Indianapolis, IN). Reproductive senescent females were used after they were retired from a breeding program (n = 10, 9–11 months, average weight 300 g). Reproductive senescent animals met our previously established criteria for this group: four to five successful pregnancies, two consecutive reproductive failures and irregular estrus cycles are determined by vaginal smears for 3 wk. The young adult group was approximately 4 months of age with a starting weight range of 225–250 g (n = 10). All animals were maintained in a constant photoperiod 12-h light, 12-h dark cycle and fed ad libitum with laboratory chow (Harlan Teklad 8604) and water. All animal procedures are in accordance with National Institutes of Health guidelines for the human care of laboratory animals and approved by the Institutional Animal Care Committee.

Surgical procedures
Ovariectomy.
Animals were anesthetized with xylazine (200 mg/kg)/ ketamine (10 mg/kg), and bilateral ovariectomies were performed using a dorsal midline incision inferior to palpated rib cage and kidneys. Ovaries were removed and 17ß-estradiol pellets (0.5 mg) 60-d time-release or control pellets (Innovative Research, Sarasota, FL) were inserted sc before closing the incision. Timed-release pellets were designed to maintain a plasma hormone level of 40–80 pg/ml (9, 11). These pellets have been used extensively in our laboratory and have resulted in physiological levels of plasma estradiol (12).

Intravenous Evans dye injections.
Twenty-one days after ovariectomy, all animals were anesthetized with xylazine/ketamine and were kept in a heating pad set at 37 C to maintain body temperature. Animals were placed in dorsal recumbency, and a midventral incision was made in the region of the neck. Skin was freed from underlying fascia by blunt end dissection, and neck muscles were gently dissected to reveal the jugular vein as it passes under the cranial end of the pectoralis major muscle. The concentration of Evans blue was determined in pilot experiments (using 15 additional animals) using a range of doses (15–30 mg/kg body weight) and with different time durations (15–60 min). Maximum dye incorporation was seen after 45 min. All animals received a similar dose of Evans blue dye, which was 15 mg/kg body weight, in a 25 mg/ml solution. Forty-five minutes after dye injection, the thoracic cavity was exposed and 300 µl of blood were collected directly from the left ventricle. Immediately after the blood withdrawal, animals were transcardially perfused with PBS and decapitated. The brains were excised rapidly and the olfactory bulbs, hippocampi, and pituitary glands were dissected out, gently blotted, weighed, and dried at 55 C overnight.

Dye concentration in brain tissue was measured by a fluorescent assay, using modifications of previously reported methods (16, 17). Dried tissues were crushed in 50% trichloroacetic acid solution, centrifuged, and the supernatant was recovered. The supernatant was diluted with 95% ethanol (1:3) for analysis. Samples and standards were loaded in a 96-well, flat-bottom, black-walled plate and samples read in a fluorescence plate reader (Bio-Tek, Winooski, VT). Tissue dye concentration was quantified from a linear standard curve plotted from known amounts of Evans blue dye dissolved in the same solvent. The concentration of dye was normalized to tissue wet weight.

Because withdrawal of significant amount of blood adversely affects blood pressure and consequently might affect extravasation of dye, it was not deemed appropriate to remove the volume of blood required for plasma estradiol assays. Note that a small volume (300 µl) of blood was recovered to observe the presence of dye. Hence, to assess plasma estradiol concentration, a similar group of young adult and reproductive senescent animals were ovariectomized and replaced with estrogen and control pellets from the same lot as the dye-injected animals. Animals were decapitated, trunk blood was collected, and plasma was separated. Plasma estradiol level was measured using a competitive binding enzyme immunoassay kit (Diagnostic System Laboratories, Inc., Webster, TX). This kit was previously validated using vendor-provided standards as well as in-house plasma samples that were previously assayed with traditional RIA kits from the same vendor. Virtually identical results were obtained from RIAs and ELISAs in our in-house plasma samples. Furthermore, values obtained in the plasma samples of the present study were similar to values obtained in our previous studies (12, 18). In previous studies, we have also reported that ovariectomy and estrogen replacement vs. control pellet replacement results in characteristic body weight gain (or loss). Hence, body weights at the beginning and end of the study were carefully recorded for animals used in the dye study.

Statistical analysis.
Results are presented as mean ± SEM for each group (n = 5). Group differences were estimated by a two-way ANOVA for each brain region with planned post hoc comparisons. Group differences were considered significantly different at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Plasma estradiol concentration was significantly increased in estradiol pellet replaced animals of both age groups (main effect of hormone treatment F1,16: 6.79, P < 0.05). Mean plasma estradiol levels were 38.36 ± 8.66 pg/ml for estrogen pellet-replaced animals compared with 11.74 ± 7.5 pg/ml for placebo control animals. There was no main effect of age on plasma estradiol levels (F1,16: 2.5 P > 0.05). Estrogen treatment to young adult and reproductive senescent animals was also determined by weight gain. There was a main effect of hormone treatment (F1,16: 128.575, P < 0.05), such that animals that were ovariectomized and replaced with estrogen had an average weight loss of 13 ± 9.61 g in young adults and 2.2 ± 5.56 g in reproductive senescent females, whereas animals replaced with a control pellet had an average weight gain of 63 ± 10.18 g (young adult) and 41 ± 8.06 g (reproductive senescent). This pattern of weight loss and gain is similar to that seen in our previous studies with estrogen and control pellet replacement (11, 12).

Evans blue dye concentration was significantly higher in the olfactory bulb of reproductive senescent animals compared with young adults (F1,16: 32.51, P < 0.05; Fig. 1Go), indicating increased dye extravasation. There was no main effect of estrogen (F1,16: 2.78; P > 0.05), but planned post hoc comparisons between estrogen-replaced and control pellet-replaced animals of the same age group indicate that estrogen replacement to ovariectomized young adults significantly reduced the extravasation of Evans blue dye in the olfactory bulb (P < 0.05), whereas there was no significant change in dye concentration in reproductive senescent animals with estrogen treatment.



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  		FIG. 1. Concentration of Evans blue dye in the olfactory bulbs of estrogen (Est) and control (Ctrl) pellet-replaced young adult (YA) and reproductive senescent (RS) rats. Dye extravasation into the olfactory bulb was greater in reproductive senescent animals compared with young adult females (**, main effect of age, P < 0.05). Estrogen treatment decreased dye concentration in young rats but had no effect on dye concentration in reproductive senescent animal. Results are expressed as mean ± SEM (n = 5/group; *, P < 0.05).

 
A similar effect was observed in hippocampus of the two age groups studied. The concentration of dye in the hippocampus was greater in senescent females compared with young adults (F1,16: 55.378, P < 0.05; Fig. 2Go). There was no main effect of hormone (F1,16: 0.778, P > 0.05) but a significant age X hormone interaction effect (F1,16: 11.35, P < 0.05). Planned post hoc comparisons between estrogen-replaced and control pellet-replaced animals of the same age group indicate that estrogen replacement decreased the permeability of Evans blue in the hippocampus of young adult animals (P < 0.05) while increasing dye extravasation in reproductive senescent females (P < 0.05).



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  		FIG. 2. Concentration of Evans blue dye in the hippocampus of estrogen (Est) and control (Ctrl) pellet-replaced young adult (YA) and reproductive senescent (RS) rats. Dye extravasation in the hippocampus was greater in reproductive senescent animals compared with young adults (**, main effect of age, P < 0.05). Estrogen treatment decreased dye concentration in young rats and increased dye accumulation in senescent animals. Results are expressed as mean ± SEM (n = 5/group; *, P < 0.05).

 
In the pituitary gland, there was a 10-fold higher amount of dye compared with the other tissues studied, which was expected because this is a circumventricular organ. Moreover, there was no difference in the amount of Evans blue dye in young and senescent pituitaries with or without estrogen replacement (overall F3,16: 1.246, P > 0.05; Fig. 3Go).



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  		FIG. 3. Concentration of Evans blue dye in the pituitary of estrogen (Est) and control (Ctrl) pellet-replaced young adult (YA) and reproductive senescent (RS) rats. No difference in the amount of dye was seen in young rats and senescent animals. Estrogen had no effect on dye accumulation at either age. Results are expressed as mean ± SEM (n = 5/group).

 
Because of the weight differences between the groups, and the fact that dye volume is normalized to body weight, the following comparisons were made to ensure that the volume of dye injected did not affect the amount of dye that was transferred into the brain. First, comparisons of pituitary dye accumulation indicate no group differences in dye transfer to this region, although these groups vary in their body weights. The second comparison was between a young and aging group where the mean body weights were similar, namely the ovariectomized, control pellet young adults (300 + 7.73 g) and ovariectomized estrogen-replaced senescent (299.6 + 11.21 g) females. These animals therefore received similar amounts of dye; however, there was a significant difference in the amount of dye transferred to the bulb (1.82 + 0.14 (young) vs. 3.13 + 0.46 (aging), P < 0.05) and hippocampus (0.75 + 0.17 (young) vs. 2.57 + 0.12 (aging), P < 0.05) of these two groups, indicating that body weight per se does not affect dye transfer or accumulation.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present data indicate that permeability of the blood-brain barrier as determined by Evans dye content is increased in reproductive senescent females and further support our previous data that estrogen replacement is beneficial when given to young adult animals but not to senescent females. Our previous studies show that estrogen replacement increases trophic support in the forebrain in young adults (11) and acts as an antiinflammatory after brain injury (12). In the present study, estrogen replacement to young adult females decreases transfer of dye across the blood-brain barrier in the olfactory bulb and hippocampus, areas that are susceptible to inflammation and neuronal loss in Alzheimer’s disease (19, 20). On the other hand, estrogen replacement to reproductive senescent animals either has no effect or increases permeability, as in the hippocampus, suggesting a mechanism by which the hormone may act to increase neurodegeneration. No age- or hormone-related differences in dye accumulation were seen in the pituitary, which is not protected by a blood-brain barrier, and consequently greater dye transfer was also seen in this region. These findings argue that endothelial cells, a principal component of the blood-brain barrier, may be altered with reproductive aging and, furthermore, that these cellular alterations may result in differential hormonal effects that may explain why estrogen replacement is not neuroprotective to older, acyclic females.

Transport of molecules across the blood-brain barrier can occur transcellularly, mediated by active, energy-dependent transporters, and can also occur through paracellular routes, via openings in the tight junctions between endothelial cells. Evan’s blue dye, which binds serum albumin, may pass through openings in the tight junctions between endothelial cells, although its primary route of transfer is thought to be via a nonspecific vesicular transport because its permeability is sensitive to temperature and labeled albumin can be detected in brain endothelial cells (21). Increased transfer in the reproductive senescent females may therefore result from chronic leakiness in the tight junctions of endothelial cells, or from increased nonspecific vesicular transfer. Aging-related changes in the blood-brain barrier of the rat include decreases in endothelial cell number (22) and decreases in capillary diameter in the rat cortex (23) with a compensatory increase in endothelial cell length. Vesicular transport is also susceptible to aging, as in the case of decreased glut-1 glucose transporter with age, although paradoxically, there are aging-related increases in ß-adrenergic transporters (24). Although the present data indicate that blood-brain barrier permeability is increased in senescent females, future studies will need to distinguish whether para- and transcellular mechanisms are affected.

Increased permeability of the blood-brain barrier may also signal a greater potential for leukocyte infiltration into the brain and increased local inflammation after injury, and consequently increased neuronal death. Disruption of blood-brain barrier and consequent migration of leukocytes into brain is seen in common neurologic conditions such as Alzheimer’s disease, multiple sclerosis, and HIV-associated dementia (25, 26). In an animal model of Alzheimer’s disease (TG2576 mice), increased albumin uptake was reported in the brains of aged TG2576 mice, compared with wild-type controls (27). Moreover, these blood-brain barrier changes were noted in the cerebral cortex well before the onset of the disease-related phenotype, suggesting that increased permeability may be an early event in the neurodegenerative changes associated with the disease. The regions examined in this study were specifically selected based on their vulnerability in Alzheimer’s disease. The present data suggest that estrogen is uniquely positioned to influence recruitment of circulating immune cells to these key brain regions, which may influence the survival of neurons in these regions.

The present data also provide a complex picture of estrogen action on the blood-brain barrier, indicating that the hormone promotes barrier integrity in young adults and promotes region-specific leakiness in reproductive senescent animals. 17ß-Estradiol has been reported to increase glucose uptake and transport in the brain (28, 29) and reduce ischemia (30) and vascular endothelial growth factor-induced (31) leakiness of the blood-brain barrier in the cerebral cortex. Oral conjugate estrogens also reduce vascular lesions and leukocyte permeability caused by A-ß 40 and A ß-42 infusions (32). On the other hand, ethinyl estradiol, a synthetic estrogen commonly used in birth control pills, increases permeability of the brain to albumin (33), water (34), inulin, and sucrose (35). The present data are therefore consistent with the previously described effects of 17ß-estradiol on the blood-brain barrier in young adult females, although to our knowledge this is the first report of estrogens effects on the reproductive senescent blood-brain barrier.

The present data also support the conclusions of the recent large-scale Women’s Health Initiative Memory Study, which did not recommend estrogen replacement to older women to prevent dementia (36). Estrogen replacement was also not beneficial to patients with mild to moderate AD (37). The Cache County prospective study of the correlation between estrogen use and AD stressed that the risk for AD decreased only with former (earlier) use of estrogen and not with current use, unless the current use was of prolonged duration (38). Although the human menopause and the rodent reproductive senescence are not strictly equivalent, the present data, together with our previous studies (11, 12), make a compelling case that there is a critical window when estrogen replacement is neuroprotective and that estrogen replacement at later time points may be ineffective, at best, and deleterious, at worst.


   Acknowledgments
 
We thank Dr. Tom Champney and Vanessa Nordell for technical assistance with surgical procedures.


   Footnotes
 
This work was supported by National Institutes of Health (AG19515) and an Investigator Initiated Research Grant (02-3853) from the Alzheimer’s Association.

Received July 29, 2004.

Accepted for publication September 27, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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L. B. J. Morales, K. K. Loo, H.-b. Liu, C. Peterson, S. Tiwari-Woodruff, and R. R. Voskuhl
Treatment with an estrogen receptor alpha ligand is neuroprotective in experimental autoimmune encephalomyelitis.
J. Neurosci., June 21, 2006; 26(25): 6823 - 6833.
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D. B. Dubal, S. W. Rau, P. J. Shughrue, H. Zhu, J. Yu, A. B. Cashion, S. Suzuki, L. M. Gerhold, M. B. Bottner, S. B. Dubal, et al.
Differential Modulation of Estrogen Receptors (ERs) in Ischemic Brain Injury: A Role for ER{alpha} in Estradiol-Mediated Protection against Delayed Cell Death
Endocrinology, June 1, 2006; 147(6): 3076 - 3084.
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