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Biology of Reproduction 63, 982-985 (2000)
© 2000 Society for the Study of Reproduction, Inc.

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Estradiol Protects Against Ischemic Brain Injury in Middle-Aged Rats1

Phyllis M. Wise2,a, and Dena B. Dubala

a Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0298


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Several clinical studies suggest that estradiol acts as a potent growth and protective factor in the adult brain. Postmenopausal women experience permanent hypoestrogenicity and suffer from increased risk of brain injury associated with neurodegenerative diseases such as stroke and Alzheimer's disease. Estrogen replacement therapy appears to decrease the risk and severity of these neurodegenerative conditions. Studies using animal models have shown that estradiol exerts similar effects in rodents and can enhance cell survival and induce synaptic plasticity. Therefore, we undertook studies to assess whether estradiol treatment can decrease brain injury and cell death induced by an experimental model of ischemia and whether aging animals remain responsive to the protective effects of estradiol. We will review results from recent studies that demonstrate that 1) in young animals, estrogens exert profound protective effects against ischemic brain injury induced by cerebral artery occlusion and 2) the response of aging animals has been tested with varying results. We will discuss and compare our experimental findings that utilize a permanent cerebral artery occlusion model and physiological levels of estradiol replacement therapy in young and middle-aged rats with those of previous studies. These observations provide important insights into the potential protective actions of estrogen replacement therapy on age- and disease-related processes in the brain.

aging, apoptosis, central nervous system, estradiol, estradiol receptor


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Recent studies highlight the importance of trophic and protective effects of estrogen in the brain. Initially, the trophic effects of estrogen were thought to occur exclusively during development and the early neonatal period. Toran-Allerand [1] found that estradiol enhanced neurite outgrowth and arborization of neuritic branches in organotypic cultures of the rodent brain. More recent evidence suggests that estradiol also exerts these actions during adulthood [2, 3]. Estradiol promotes formation of functional dendritic spines [4, 5] and stimulates synaptogenesis [6]. Specifically, estradiol and progesterone regulate the number of spines on the dendrites of CA1 pyramidal cells in ovariectomized (OVX) rats [7]. Furthermore, the number of spines fluctuates during normal estrous cycles, peaking on proestrus, when estradiol levels are high [8].

Clinical and epidemiological studies demonstrate that estradiol influences cognition, the incidence and progression of Alzheimer's disease, and the severity of injury associated with cerebrovascular stroke [3, 9–12]. These studies suggest that estrogen replacement therapy 1) improves cognition in young or aging women, 2) decreases the risk of Alzheimer's disease, and 3) decreases the risk or the severity of neurodegenerative decline associated with cerebrovascular stroke.

Animal models have been developed to examine estradiol's ability to protect against brain injury. Methods have been developed to mimic cerebral ischemia that occurs with stroke by blocking of one or more cerebral arteries to produce a reproducible infarct in the brain. These experimental manipulations provide convincing evidence that estradiol is a neuroprotective factor. Female gerbils exhibit attenuated neuropathology compared to males after unilateral carotid artery occlusion [13]. Rats exhibit similar sex-related differences: females have significantly smaller areas of infarction compared to intact males [14]. Furthermore, estrogen replacement in OVX rats significantly decreases ischemic injury compared to vehicle-treated controls [14–17]. Most of these studies have used young animals in which the steroidal milieu has been experimentally manipulated rather than in animals who have undergone normal aging. It is important to note that stroke rarely occurs in young women but increases in postmenopausal women; therefore, it is important to assess whether older animals remain responsive to the protective actions of estrogen.

Most previous studies have used pharmacological doses of estradiol to examine its ability to protect the brain against injury. Our studies have focused on the ability of physiological concentrations to protect. The goal of these studies was to use an in vivo model of permanent, focal ischemia to assess whether 1) physiological levels of estradiol attenuate brain injury and 2) whether middle-aged rats remain responsive to these modest levels of estradiol. We will compare our findings with those of other studies that have utilized pharmacological levels of steroid replacement and have examined whether older animals continue to exhibit gender-related differences in the ability to withstand brain injury.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals and Experimental Treatments

Young (3–4 mo) and middle-aged (9–11 mo) female Sprague-Dawley rats were ovariectomized. Immediately after ovariectomy, Silastic capsules were implanted subcutaneously. Animals received capsules filled with vehicle (sesame oil), or 17ß-estradiol (1 mg/ml). This dose of estradiol was chosen because our previous study demonstrated that plasma levels of hormone were within the range observed during a normal estrous cycle [16]. One week later, rats were anesthetized and the right middle cerebral artery (MCA) was permanently occluded using a method modified from Longa et al. [18] as described in detail in our previous publication [16]. A 4/0 black, monofilament suture (Ethicon) was used in young rats and a 3/0 filament was used in middle-aged rats to achieve the same decrease in blood flow as monitored by laser Doppler flowmetry (data not shown).

Quantification of Infarct Size

Rats were killed 24 h after the onset of ischemia. Brains were removed and sectioned into 1-mm slices. Alternate slices were stained for 15 min in 2% triphenyltetrazolium chloride (TTC; Fisher Scientific, Fairlawn, NJ) [19] and then fixed in 10% buffered formalin. Total, cortical, and striatal ischemic injury was quantified using an NIH Image program on a Bioquant 052 system, and the size of the infarct is expressed as volume (mm3).

Data Analysis

All data are expressed as mean ± SEM. Infarct volumes were analyzed with one-way ANOVA. Post-hoc analyses were carried out with the Newman-Keuls test. All differences were considered significant at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Figure 1 shows a representative TTC-stained brain section from an OVX oil-treated and an OVX estradiol-treated young rat that underwent permanent middle cerebral artery occlusion. The figure clearly shows that physiological levels of estradiol significantly decreased the injured area of the brain, an effect that was most apparent in the cerebral cortex. Total infarct area was calculated in sequential 1-mm brain sections of groups (n = 8–11) of young rats (Fig. 2). These data demonstrate that estradiol protects regions of the brain from the most rostral to caudal aspects of the injury. We found that pretreatment with estradiol was necessary in order to protect the brain from ischemic injury and that hormone replacement at the time of MCA occlusion did not influence the size of the infarct (data not shown) [16].



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  		FIG. 1. Representative 1-mm-thick brain section from an oil- (left) and an estradiol-treated (right) rat brain after permanent cerebral ischemia. Infarcted tissue is white while live tissue is darkly stained by TTC. Estradiol pretreatment protects young female rat brains from ischemic brain injury



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  		FIG. 2. Infarct volume of alternate sequential 1-mm-thick brain sections from oil- (clear bars) and estradiol-treated (solid bars) rat brain. Estradiol significantly reduced infarct volume from the most rostral to caudal extent of the infarct (P < 0.05). Mean ± SEM, n = 6–9 rats

Using this experimental paradigm, we tested whether middle-aged rats remain responsive to the protective effects of estradiol. Figure 3 demonstrates that subcutaneous implantation of Silastic capsules that produce estradiol levels of approximately 75 pg/ml protects middle-aged rats in a manner that is strikingly equivalent to young rats. The total infarct area and cortical infarct area were significantly smaller in estradiol-treated compared to vehicle-treated rats, regardless of age.



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  		FIG. 3. Total (top panel), cortical (middle panel), and striatal (bottom panel) infarct volume in oil- (clear bars) and estradiol-treated (solid bars) in young and middle-aged rats. Estradiol protected in both young and middle-aged rats (P < 0.05). Mean ± SEM, n = 6–11 rats per experimental group


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
As far as we are aware, this is the only study that focuses on the middle-aged period of life (9–12 mo) when reproductive cycles are beginning to become irregular and when the constant estrous vaginal smear pattern becomes more common. Our data clearly demonstrate that estradiol greatly attenuates the extent of brain damage induced by permanent cerebral occlusion in both young and middle-aged rats. Estradiol replacement therapy reduced infarct size by 50% in the cerebral cortex, while the effect in the striatum was not significant. These findings of undiminished responsiveness to estradiol in middle-aged rats were somewhat unexpected because every other endpoint of responsiveness that we have measured in the hypothalamic/pituitary axis of young compared with middle-aged rats has revealed attenuated responses to this hormone. These include a decreased ability of estradiol to induce LH surges [20, 21] and diurnal rhythmicity in the neurotransmitters that are thought to mediate this response [20, 22], decreased ability of estradiol to stimulate progesterone receptor binding in hypothalamic regions [23], and decreased ability of estradiol to modulate diurnal expression of multiple genes in the hypothalamus [24, 25]. The equivalent neuroprotection induced by estradiol in young and aging rats was also somewhat unexpected because we have shown that the level of estrogen receptor-beta mRNA expression that correlates with protective effects of estradiol [26] is slightly, but significantly, suppressed in the cortex of middle-aged rats (unpublished).

Some, but not all, previous studies that have attempted to use similar methods in considerably older rats have had limited success [27, 28] due to the rigidity of the MCA in older rats and the consequent difficulty of occluding the artery. Thus, other methods of experimental brain injury have been used to attack these questions in older animals [29, 30]. Older animals exhibit greater cerebral infarction when focal ischemia is performed [31–34] but global ischemia has inconsistent effects and may be related to several variables including strain [35], sex [29, 34, 36], experimental conditions [36], and location of the infarct [34].

Numerous studies have utilized models of cerebrovascular stroke to assess whether males and females are equally vulnerable to ischemic brain injury [13, 14] and whether estrogens influence the extent of injury [15, 16, 26, 28, 37–42]. Differences among the experimental approaches have revealed that estrogens appear to utilize diverse mechanisms to protect the brain against injury. Most of these studies have utilized rats; however, other rodent models [13, 41, 43] have been utilized as well. The majority of studies have administered pharmacological doses of estradiol [15, 38, 39, 41, 42, 44]. Some of these studies did not provide plasma estradiol levels, but used doses known to produce up to 100-fold higher than observed during the estrous cycle. Few studies have probed the efficacy of lower levels [16, 26, 40] of hormone replacement. We have previously shown that both low physiological (~15–20 pg/ml) and high physiological (~60–80 pg/ml) levels of estradiol afforded equivalent protection against ischemic brain injury [16]. Finally, some studies have utilized a transient model of cerebral artery occlusion [13, 14, 17, 28, 39, 40], which means that estradiol may be acting to protect against the initial ischemia or against reperfusion injury. Whereas, we [16, 26] and others [15, 42, 45] have utilized a permanent MCA occlusion model. Permanent occlusion leads to a more severe and prolonged decrease in cerebral vascularization of the brain and limits the potential ameliorative effects of estradiol to its ability to prevent the repercussions of decreased blood flow.

Although some discrepancies exist among the results of the numerous studies that have been performed, together these studies allow some general conclusions regarding potential mechanisms of estrogen's protective effects. Previous studies have shown that pharmacological levels of estradiol can protect the brain against ischemic injury in transient models of MCA occlusion [15, 37–39, 42]. In some of these studies, pretreatment was not necessary [14, 15, 42]. We suspect that when the doses are high and/or when the blood flow is decreased for short periods of time, estradiol may act via nonreceptor-mediated mechanisms, such as decreasing free radical generation [46–49], increasing blood flow [14, 37, 39, 50], decreasing intracellular calcium accumulation [38], inhibition of excitatory amino acid-induced excitotoxicity [48, 49, 51–53], or rapid activation of second messenger signaling pathways [54–57]. On the other hand, more physiological levels of estrogen replacement are likely to utilize estrogen receptors ({alpha} and/or ß estrogen receptors) that involve changing gene transcription. Estradiol is known to enhance expression of neurotrophins, neurotrophin receptors [58–60], and influence the balance of expression of apoptotic/antiapoptotic genes [26, 61–63], and growth factors that influence synaptogenesis [64, 65].

In summary, our results clearly establish that estradiol plays a neuroprotective role in the injured brain in both young and middle-aged rats. The data strongly imply that older women may also benefit from the protective effects of estrogen replacement therapy. Clearly, many factors must be taken into consideration before such assumptions can be proven.


   FOOTNOTES
 
First decision: 17 February 2000.

1 Supported in part by NIH grants AG02224 and AG00242 (P.M.W.) and the Glenn Foundation/American Federation for Aging Research (D.B.D.). Back

2 Correspondence. FAX: 606 323 1070; pmwise1{at}pop.uky.edu Back

Accepted: May 4, 2000.

Received: January 13, 2000.


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