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Protective Effects of Estrogen and Selective Estrogen Receptor Modulators in the Brain¹

^a Institute of Molecular Medicine and Genetics, Program in Neurobiology, and Department of Neurology, Medical College of Georgia, Augusta, Georgia 30912

	ABSTRACT

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Within the last few years, there has been a growing interest in the neuroprotective effects of estrogen and the possible beneficial effects of estrogen in neurodegenerative diseases such as stroke, Alzheimer disease, and Parkinson disease. Here, we review the progress in this field, with a particular focus upon estrogen-induced protection from stroke-induced ischemic damage. The important issue of whether clinically relevant selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene and estrogen replacement therapy can exert neuroprotection is also addressed. Although the mechanism of estrogen and SERM neuroprotection is not clearly resolved, we summarize the leading possibilities, including 1) a genomic estrogen receptor-mediated pathway that involves gene transcription, 2) a nongenomic signaling pathway involving activation of cell signalers such as mitogen-activated protein kinases and/or phosphatidylinositol-3-kinase /protein kinase B, and 3) a nonreceptor antioxidant free-radical scavenging pathway that is primarily observed with pharmacological doses of estrogen. The role of other potential mediatory factors such as growth factors and the possibility of an astrocyte role in neuroprotection is also discussed.

estradiol, neuroendocrinology, steroid hormones

	INTRODUCTION

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Recently, there has been a growing interest in the actions and functions of 17ß-estradiol (17ß-E₂) and selective estrogen receptor modulators (SERMs) in the brain, particularly in whether they are neuroprotective for such neurodegenerative conditions as stroke, Alzheimer disease, and Parkinson disease. The concept that 17ß-E₂ and SERMs (such as the clinically relevant tamoxifen and raloxifene) may be neuroprotective has only begun to gain momentum within the last decade, and the field is thus quite young. Nevertheless, 17ß-E₂ has been shown in an impressive number of studies to be protective against a wide variety of death-inducing agents both in vitro and in vivo, and initial reports are beginning to appear of similar neuroprotective effects of SERMs.

Collateral support for a neuroprotective role of endogenous 17ß-E₂ has also arisen from the observations of greater brain damage observed in males than in females and in ovariectomized (OVX) compared with intact female animals in ischemic stroke models [1–8]. As women age and enter menopause, they lose most of their ability to produce 17ß-E₂ because of depletion of ovarian follicles, and 17ß-E₂ blood levels in postmenopausal women thus are typically only 1% of those observed in normally cycling young women. This 17ß-E₂-deplete state in postmenopausal women has been correlated with increased incidence of stroke, cognitive defects, hot flashes, mood changes, and early onset and severity of Alzheimer disease, although a causative relationship has not been firmly established. As the field of neurobiological and neuroprotective actions of estrogens has matured, it has approached a point where a review of the area would be beneficial. Hence, the goal of this article is to assess the state of the field of 17ß-E₂ and SERM neuroprotection. To maintain focus, we concentrate primarily on ischemic stroke damage and 17ß-E₂/SERM protection.

	EVIDENCE FOR A NEUROPROTECTIVE ROLE FOR 17ß-E2 AND SERMs

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17ß-Estradiol

One of the first reports to hint at a possible sex steroid-based neuroprotection mechanism was published over a decade ago. In that study, female gerbils experienced a lower incidence and less severe brain damage following carotid artery occlusion than did male gerbils [9]. This gender difference in ischemic stroke damage was subsequently extended to the rat through studies that showed that intact adult female rats sustain lower mortality and less neuronal damage than do age-matched males following middle cerebral artery occlusion (MCAO) [2]. The possibility that the gender-based protection observed in females is due to an ovarian factor was suggested by studies in which ovariectomy was shown to eliminate the protective effect observed in females following cerebral ischemia [2]. Although there are many products secreted by the ovary, there is now abundant evidence that the major neuroprotective factor from the ovary responsible for the gender-based difference in ischemic stroke damage is 17ß-E₂. Work by a large number of groups has shown that exogenous administration of 17ß-E₂ dramatically reduces infarct volume following MCAO in OVX female rats [1, 3–6], in male rats [7], and in aged, reproductively senescent female rats [10], which represent a model of female menopause. The doses of 17ß-E₂ used in these studies did not influence cerebral blood flow, implying that the neuroprotective effect of 17ß-E₂ occurs directly at the level of the brain rather than involving the vasculature [6, 11]. Progesterone replacement in OVX rats did not give similar protection from MCAO-induced ischemic damage, as was observed with 17ß-E₂ replacement [12].

Additional support for a neuroprotective role of 17ß-E₂ has come from studies showing that serum 17ß-E₂ levels are inversely correlated with ischemic stroke damage in female rats and from the observation that female animals treated with an antiestrogen compound, ICI182,780, have significantly enhanced stroke infarct size as compared with vehicle-treated female rats [13, 14]. There are also recent reports that the most frequently prescribed estrogen replacement hormones in the United States, conjugated equine estrogens, are neuroprotective against neuronal cell death induced by ß-amyloid(25–35), hydrogen peroxide, and glutamate and induce neurite outgrowth in cortical, hippocampal, and basal forebrain neurons [15, 16]. This finding raises the exciting possibility that estrogen replacement therapy may also have beneficial neurotrophic and neuroprotective effects on the brain.

Selective Estrogen Receptor Modulators

Although estrogen replacement therapy is widely prescribed, it can have certain disadvantages because of its multiple effects in the body. For instance, 17ß-E₂ can have undesired stimulatory effects on the breast and uterus, and thus estrogen replacement therapy has been associated with an increased risk of developing breast and uterine cancers. In an attempt to circumvent the limitations of estrogen replacement therapy, there has been intense interest in the development and therapeutic use of nonsteroidal SERMs. Although an ideal SERM has yet to be developed, theoretically it would exhibit antagonist activity in the breast and uterus and agonist activity in the cardiovascular system, bone, and brain. Of the SERMs available today, tamoxifen and raloxifene are approved by the Food and Drug Administration for the treatment/prevention of breast cancer and osteoporosis, respectively. Recently, several laboratories have explored whether these clinically relevant SERMs or analogues thereof could exert neuroprotective actions in animal models of cerebral ischemia. In one study, pretreatment with LY353381.HCl, a raloxifene analogue, protected the caudate-putamen region of the brain of OVX female rats in an ischemia-reperfusion model of ischemic stroke [17]. The effect of LY353381.HCl was independent of cerebral blood flow changes, indicating a potential direct neuroprotective effect of this SERM in the brain. Tamoxifen also appears to be neuroprotective. In recent work [18–20], it significantly reduced infarct size in permanent MCAO and transient occlusion/reperfusion models of cerebral ischemia. Like the raloxifene analogue, the protective effect of tamoxifen was independent of cerebral blood flow changes, indicating a potential direct neuroprotective effect of this SERM in the brain. Tamoxifen was also recently shown to protect the striatum against 1-methyl-4-phenylpyridine-induced toxicity, suggesting that its protective abilities may extend to regions of the brain that are known to be affected in Parkinson disease [21]. In addition to exerting neuroprotection, there is increasing evidence that SERMs may also be neurotrophic. For instance, tamoxifen increased synaptic density in the hippocampus of OVX rats, and raloxifene enhanced neurite outgrowth of PC12 cells in vitro [22, 23]. These studies suggest that SERMs can exert agonist effects in the brain and that clinically relevant SERMs such as tamoxifen and raloxifene may have heretofore unrecognized but potentially clinically important neuroprotective and neurotrophic effects on the brain.

Several mechanisms have been proposed to explain how 17ß-E₂ and SERMs may protect the brain (Fig. 1). These proposals include 1) a genomic estrogen receptor (ER)-mediated mechanism, 2) a nongenomic mechanism involving mitogen-activated protein kinase (MAPK) and/or phosphotidylinositol-3-kinase (PI3K) signaling, and 3) a receptor-independent antioxidant free-radical scavenging mechanism. The first two mechanisms, genomic and nongenomic signaling, can be observed at low physiological doses of 17ß-E₂. In contrast, the third mechanism (antioxidant free-radical scavenging) is only observed at high nonphysiological doses of 17ß-E₂. Thus, the first two mechanisms are thought to underlie physiological neuroprotection by 17ß-E₂, whereas the third mechanism may come into play if high pharmacological doses of estrogen are used. These three potential mechanisms and the evidence supporting each are discussed below.

View larger version (105K): [in this window] [in a new window]   FIG. 1. Possible mechanisms of estrogen/SERM neuroprotection. See text for full description. SERM, Selective estrogen receptor modulator; ER, estrogen receptor; MAPK, mitogen activated protein kinase; AKT, protein kinase B

	EVIDENCE FOR AN ER-MEDIATED GENOMIC ACTIVATION MECHANISM

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Genomic Activation

Evidence suggesting a genomic mechanism of action for 17ß-E₂ in its neuroprotective effects has arisen from several areas. First, Wise and coworkers [3] showed that pretreatment is required to observe the neuroprotective effect of 17ß-E₂ in the in vivo MCAO cerebral ischemia model. In these studies, acute pretreatment or administration of 17ß-E₂ at the time of MCAO failed to protect against brain injury, whereas 24 h of pretreatment was protective. A similar requirement for 24-h pretreatment to observe the 17ß-E₂ protective effect has also been reported in rat cortical neurons and in rat cortical explants in vitro [24, 25]. These studies suggest a genomic mechanism of 17ß-E₂ action in protecting the brain; 17ß-E₂ at physiological doses primarily exerts effects through activation of an ER and subsequently gene transcription. The precise genes regulated by 17ß-E₂ to exert its neuroprotective effect have not been identified, but 17ß-E₂ increases the expression of the antiapoptotic gene, bcl-2, in the ischemic penumbra following MCAO [26]. 17ß-Estradiol also increases bcl-2 levels in human NT2 neurons in vitro [27]. The role of bcl-2 in protection of the brain against ischemic stroke damage was recently confirmed by studies demonstrating a decreased infarct volume following MCAO in OVX transgenic mice overexpressing the bcl-2 gene as compared with wild-type OVX female mice [28].

ER Mediation

The requirement for 24-h pretreatment and the activation of gene expression by 17ß-E₂ seem to suggest a role for the ER in mediation of the neuroprotective effects of 17ß-E₂. In support of this contention, Sawada et al. [14] showed that administration of the potent ER antagonist, ICI182,780, dramatically increased infarct size in intact female rats following MCAO. Furthermore, ICI182,780 also blocked neuroprotection by low physiological doses of 17ß-E₂ (1, 10, and 30 nM) in cortical explant cultures in vitro [25]. Two ER isoforms have been identified to date, ER and ERß. Both ERs are expressed in the adult brain, and either one or both could mediate the neuroprotection by 17ß-E₂ [29, 30]. To elucidate the individual ER subtype involved in 17ß-E₂-mediated neuroprotection in vivo, specific ER knockout mice models have been used, which include ER knockout mice (ERKO) and ERß knockout mice (ßERKO). The results so far with these transgenic animal models have been somewhat contradictory.

Evidence supporting a possible mediatory role for ER in estrogen neuroprotection has come from the work of Dubal et al. [26], who demonstrated that following MCAO in rats, ER mRNA was highly upregulated in the ischemic penumbra in the presence or absence of 17ß-E₂. Furthermore, 17ß-E₂ failed to protect the brain of OVX ERKO mice [31]. In contrast, 17ß-E₂ protected the brain of OVX ßERKO mice in a manner similar to that observed in OVX wild-type mice [31]. These findings, coupled with the upregulation of the ER gene following MCAO, suggest a critical role for ER in the protection of the brain by 17ß-E₂. However, these findings are in contrast to those of Sampei et al. [32], who failed to demonstrate a critical role for ER in neuroprotection following ischemic stroke. Sampei et al. found that intact wild-type and ERKO mice sustained a similar infarct volume following ischemic stroke, leading them to conclude that ER is not necessary for protection by endogenous 17ß-E₂. However, intact ERKO mice reportedly have dramatically higher serum levels of E₂ than do wild-type controls, which may complicate interpretations [33]. For instance, increased estrogen levels in the intact ERKO mice may allow a compensatory activation of the ERß subtype and/or exert a pharmacological ER-independent antioxidant effect.

Recent work has also implicated a possible role for ERß in neuroprotection. For instance, Wang et al. [34] showed that ßERKO mice experienced a significant loss of neurons coupled with astroglia proliferation in the cerebral cortex. The loss of neurons was most pronounced between the somatosensory and parietal cortex. In addition, the size of the brain of 2-yr-old, but not 2-mo-old, ßERKO mice was dramatically reduced compared with wild-type controls, suggesting that the loss of neurons occurs throughout the life of the animal rather than exclusively during the process of development. This finding contrasts with the observations in the ERKO mouse, which lacks gross brain morphological changes. As a whole, these data imply that ERß is important in the basal maintenance of neuronal survival. However, it is unclear what role if any ERß has in protecting neurons following brain injury. In a recent study by Dubal et al. [31], 17ß-E₂ was still protective against MCAO-induced stroke damage in OVX ßERKO mice, suggesting that ERß may not mediate the protective effects of 17ß-E₂. Likewise, infarct size in wild-type versus ßERKO intact mice has also been reported not to differ, but the caveats about elevated 17ß-E₂ levels in intact ßERKO mice must be considered when interpreting these findings. As a whole, the current data suggests that both ER and ERß may exert neuroprotection in the brain. Although definitive roles cannot be assigned, the findings suggest a possible role for ERß in basal neuroprotection and for ER in injury-induced 17ß-E₂-mediated protection. Further studies are needed to clarify the role(s) of the individual ER isoforms in 17ß-E₂-mediated neuroprotection.

	EVIDENCE FOR A NONGENOMIC MECHANISM FOR 17ß-E2 NEUROPROTECTION

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Although a genomic mechanism of action for 17ß-E₂ neuroprotection has been implicated in many studies, it may not be the only mechanism utilized by 17ß-E₂ to exert its neuroprotective effect. There is a growing body of evidence to suggest that a rapid induction of cell signaling pathways may play a crucial role in the actions of 17ß-E₂ in the brain. Specifically, two signaling pathways, the MAPK pathway and the PI3-K/protein kinase B (Akt) pathway have been implicated in 17ß-E₂ actions in the brain and nervous tissue, including its neuroprotective actions [35–39].

MAPK Activation

Recent studies have shown that 17ß-E₂ rapidly activates the MAPK pathway in primary neuronal cortical cultures and in organotypic cerebrocortical explant cultures [40–43]. In rat cortical neurons incubated in vitro, 17ß-E₂ induced phosphorylation of MAPK within 30 min of exposure, an effect blocked by the ER antagonist ICI182,780 [40]. The possibility that activation of the MAPK pathway by 17ß-E₂ is important for the neuroprotective actions of 17ß-E₂ was suggested by the finding that PD98059, a specific MAPK inhibitor, blocked the neuroprotective effect of 17ß-E₂ against glutamate excitotoxicity. Singh et al. [41] extended these observations to organotypic cerebrocortical explant cultures by showing that 17ß-E₂ elicited phosphorylation of MAPK within 15 min, an effect that was sustained for 2 h. However, ICI182,780 failed to inhibit the 17ß-E₂ effect in this model, suggesting that a novel ER subtype or a novel mode of action may mediate the MAPK regulatory effect of 17ß-E₂. In support of this hypothesis, 17ß-E₂ maintained the ability to induce ER activation in organotypic explant cultures derived from ERKO mice, implying ER was not involved in this effect. Further, neither 16-17ß-iodo-17ß-E₂, an ER-specific ligand, nor genistein, an ERß-selective ligand, elicited MAPK phosphorylation [42]. In addition to the potential neuroprotective effect of 17ß-E₂-induced MAPK phosphorylation in the cerebral cortex, 17ß-E₂ also was recently demonstrated to protect hippocampal neurons from excitotoxicity via the MAPK activation pathway [35, 44]. The protection of hippocampal neurons is of interest because of the postulated protective actions of 17ß-E₂ in Alzheimer disease. Cyclic changes in 17ß-E₂ have also recently been shown to be correlated with activation of brain MAPK, further suggesting a regulatory link between 17ß-E₂ and the MAPK signaling pathway in the brain [45].

PI3-K/Akt Activation

PI3-K is an enzyme responsible for phosphorylation/activation of Akt, a serine kinase that has been implicated in a variety of models as a survival factor [46, 47]. Akt phosphorylates death signals such as BAD (Bcl-2 antagonist of cell death) and glycogen synthase kinase 3ß, leading to their inactivation [47, 48]. In recent work in cultured rat cortical neurons, PI3-K was rapidly activated following treatment with low doses of 17ß-E₂ [49, 50]. Phosphorylation of Akt, a downstream target of PI3-K, was increased as early as 15 min following the addition of 17ß-E₂ and stayed elevated over basal levels up to 24 h following treatment. Activation of PI3-K was crucial for the protective effect of 17ß-E₂ against glutamate excitotoxicity, and the 17ß-E₂ protection was abolished by coadministration of the selective PI3-K inhibitor LY294002. The protection was also abolished by the coadministration of ICI182,780, suggesting that 17ß-E₂ activates PI3-K/Akt through an ICI182,780-sensitive ER. However, ICI182,780 only partially attenuated the induction of Akt phosphorylation induced by 17ß-E₂, implying that an ICI182,780-insensitive receptor may mediate PI3-K activation by 17ß-E₂. 17ß-Estradiol also phosphorylated Akt in mouse organotypic cerebral cortical explants in vitro [43]. Additionally, recent work has extended 17ß-E₂ regulation of Akt to hippocampal neurons and shown that estrogen protection against ß-amyloid-induced cell death in hippocampal neurons can be blocked by a PI3-K inhibitor [51]. Correlative studies with SERMs and Akt in the brain have not been performed, but the raloxifene analog LY117018 rapidly activated Akt in vascular endothelial cells, suggesting that a similar regulation in the brain by SERMs is possible [52].

The mechanism whereby 17ß-E₂ and SERMs can regulate PI3-K/Akt is poorly understood. However, work in Chinese hamster ovary cells has shown that raloxifene activation of Akt occurs in cells expressing ER but not in those expressing ERß [52]. Simoncini et al. [53] recently demonstrated that ER binds in a ligand-dependent fashion to the p85 regulatory subunit of PI3-K, leading the authors to suggest that there exists a nonnuclear estrogen signaling pathway involving direct interaction of ER with PI3-K. Such a pathway would be consistent with recent reports that ER can be localized at the cell membrane in addition to its well-known nuclear localization [54, 55]

	EVIDENCE FOR AN ANTIOXIDANT MECHANISM FOR 17ß-E2 NEUROPROTECTION

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Recent work suggests that 17ß-E₂ at pharmacological concentrations (the micromolar range) can act as an antioxidant [56]. The antioxidant ability of 17ß-E₂ may be mediated by the phenolic A ring of the steroid, which is a potent electron donor and free-radical scavenger and prevents lipid peroxidation-induced membrane damage [9, 56–60]. In support of a possible antioxidant protective effect of pharmacological estrogen doses, Simpkins et al. [1] recently reported that administration of pharmacological doses of 17ß-E₂ up to 90 min following ischemic stroke in rats significantly reduced infarct volume. However, administration of physiological doses of 17ß-E₂ within the same time frame failed to similarly protect the brain, suggesting a nongenomic mechanism of action for pharmacological estrogen protection. The pharmacological estrogen antioxidant effect can also be observed in vitro. Bae et al. [61] demonstrated that 17ß-E₂ at pharmacological levels protected mouse cortical neuronal cultures from cell death from various insults, including serum deprivation, FeCl₂, excitotoxicity, and Aß25–35. The protective ability was also observed with 17-E₂, which has weak estrogenic activity but possesses antioxidant activity similar to that of 17ß-E₂. A number of reports have now appeared in the literature confirming that pharmacological concentrations of 17ß-E₂ attenuate ß-amyloid-induced cell death through an antioxidant mechanism [57, 58, 62–65].

Despite the above evidence in favor of a receptor-independent mechanism of protection by 17ß-E₂, this mechanism does not appear to account for the protection observed with physiological levels of 17ß-E₂ in vivo. The antioxidant capability of 17ß-E₂ is observed following administration of high, supraphysiological doses, far exceeding the levels found under physiological conditions. Additionally, some of the protective effects observed with high doses of 17ß-E₂ are associated with vasodilation and increased blood flow. However, the protection of the brain following physiological 17ß-E₂ administration in vivo is independent of cerebral blood flow changes [3, 9]. Thus, pharmacological doses of 17ß-E₂ may be an effective clinical therapy following ischemia stroke injury, but this mechanism most likely cannot explain the well-documented protection of the brain by physiological levels of 17ß-E₂ in vivo.

	OTHER MECHANISMS?

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Although the above mechanisms represent the major focal areas of research into estrogen neuroprotection, other possible mechanisms exist and are being actively investigated by several laboratories. Preeminent among these are the possible involvement of growth factors in 17ß-E₂ neuroprotection and the potential role of other cell types such as astrocytes. With respect to growth factors, there is increasing evidence of interactions between insulin-like growth factor I (IGF-I) and estrogen in the brain. For instance, the IGF-I receptor has been reported to be necessary for 17ß-E₂ regulation of bcl-2 in the brain, and a synergistic effect has also been reported between 17ß-E₂ and IGF-I in the regulation of Akt. The interaction of estrogen and IGF-I in brain function and neuroprotection was elegantly reviewed by Cardona-Gomez et al. [66]. With regard to astrocytes, it has been known for some time that astrocytes are important in protecting neurons from cell death [67–71]. We and others [72–76] have reported that astrocytes in various regions of the brain, including hypothalamic, cortical, and hippocampal astrocytes, express ERs, suggesting that brain astrocytes may be targets for 17ß-E₂ action. 17ß-Estradiol and tamoxifen can enhance release from brain astrocytes of transforming growth factor ß, which is neuroprotective against a wide variety of death-inducing agents [69, 74, 77–81]. Thus, it has been hypothesized that 17ß-E₂ protects neurons through both indirect and direct mechanisms, and the protection involves multiple cell types and mobilization of growth factors. This intriguing possibility will certainly be an important area for future investigation.

	CONCLUSIONS AND FUTURE DIRECTIONS

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An increasing amount of data suggests a neuroprotective role for 17ß-E₂; however, the molecular mechanisms whereby 17ß-E₂ exerts these actions are unclear. Several different signaling mechanisms probably act in concert to achieve the protection observed following neuronal injury. Future investigations will determine the role of various 17ß-E₂-regulated pathways on the protection of neurons from injury. With the genomic revolution, the employment of gene chip arrays undoubtedly will aid in the elucidation of target genes and pathways regulated by 17ß-E₂ and SERMs to provide neuroprotection. The possibility that other cell types, such as astrocytes, represent an intermediary of 17ß-E₂-mediated neuroprotection will also be a fertile area for future research. Although studies of 17ß-E₂ protection in the human brain are still controversial, many studies support a role for estrogen replacement therapy in the reduction of injury associated with neurodegenerative diseases. However, estrogen replacement therapy is not a viable option for the treatment of male patients because of numerous undesirable side effects. The results from animal model studies suggest that SERMs, like 17ß-E₂, possess potent neuroprotective capability. Thus, current SERMs or newly designed SERMs may be protective and may circumvent the adverse side effects associated with estrogen replacement therapy. Future clinical studies to investigate the role of current and new SERMs in the reduction of risk and severity of neurodegeneration in humans certainly seem warranted. The investigation of estrogen neuroprotection has mushroomed in the past few years, and continued growth is expected because of high interest in the potential for treatment of a variety of important neurodegenerative diseases. The beneficial effects of SERMs on the brain that have been observed in the limited studies performed to date is exciting and undoubtedly will serve as a springboard for launching many more studies in the future both at the clinical and basic science level.

	FOOTNOTES

 
¹ This research was supported by grants (HD-28964 and AG17186 to D.W.B.) from the National Institutes of Health, NICHD, and NIA and an AFAR/Glenn Fellowship (to K.M.D.).

² Correspondence: Darrell W. Brann, Institute of Molecular Medicine and Genetics, Neurobiology Program, 1120 15th Street, Augusta, GA 30912. FAX: 706 721 8685; dbrann{at}mail.mcg.edu

Received: 22 January 2002.

First decision: 8 March 2002.

Accepted: 25 March 2002.

	REFERENCES

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1. Simpkins JW, Rajakumar G, Zhang YQ, Simpkins CE, Greenwald D, Yu CJ, Bodor N, Day AL. Estrogens may reduce mortality and ischemic damage caused by middle cerebral artery occlusion in the female rat. J Neurosurg 1997 87:724-730[Medline]
2. Alkayed NJ, Harukuni I, Kimes AS, London ED, Traystman RJ, Hurn PD. Gender-linked brain injury in experimental stroke. Stroke 1998 29:159-166[Abstract/Free Full Text]
3. Dubal DB, Kashon ML, Pettigrew LC, Ren JM, Finklestein SP, Rau SW, Wise PM. Estradiol protects against ischemic injury. J Cereb Blood Flow Metab 1998 18:1253-1258[CrossRef][Medline]
4. Shi J, Panickar KS, Yang SH, Rabbani O, Day AL, Simpkins JW. Estrogen attenuates over-expression of ß-amyloid precursor protein messenger RNA in an animal model of focal ischemia. Brain Res 1998 810:87-92[CrossRef][Medline]
5. Zhang YQ, Shi J, Rajakumar G, Day AL, Simpkins JW. Effects of gender and estradiol treatment on focal brain ischemia. Brain Res 1998 784:321-324[CrossRef][Medline]
6. Rusa R, Alkayed NJ, Crain BJ, Traystman RJ, Kimes AS, London ED, Klaus JA, Hurn PD. 17ß-Estradiol reduces stroke injury in estrogen-deficient animals. Stroke 1999 30:1665-1670[Abstract/Free Full Text]
7. Toung TJK, Traystman RJ, Hurn PD. Estrogen-mediated neuroprotection after experimental stroke in males. Stroke 1998 29:1666-1670[Abstract/Free Full Text]
8. Alkayed NJ, Murphy SJ, Traystman RJ, Hurn PD. Neuroprotective effects of female gonadal steroids in reproductively senescent female rats. Stroke 2000 31:161-168[Abstract/Free Full Text]
9. Hall ED, Pazara KE, Linseman KL. Sex differences in postischemic neuronal necrosis in gerbils. J Cereb Blood Flow Metab 1991 11:292-298[Medline]
10. Alkayed NJ, Crain BJ, Traystman RJ, Hurn PD. Estrogen-mediated neuroprotection in reproductively senescent rats. Stroke 1999 30:274
11. Dubal DB, Wise PM. Neuroprotective effects of estradiol in middle-aged female rats. Endocrinology 2001 142:43-48[Abstract/Free Full Text]
12. Murphy SJ, Traystman RJ, Hurn PD, Duckles SP. Progesterone exacerbates striatal stroke injury in progesterone-deficient female animals. Stroke 2000 31:1173-1178[Abstract/Free Full Text]
13. Liao SL, Chen WY, Kuo JS, Chen CJ. Association of serum estrogen level and ischemic neuroprotection in female rats. Neurosci Lett 2001 297:159-162[CrossRef][Medline]
14. Sawada M, Alkayed NJ, Goto S, Crain BJ, Traystman RJ, Shaivitz A, Nelson RJ, Hurn PD. Estrogen receptor antagonist ICI182,780 exacerbates ischemic injury in female mouse. Stroke 2000 20:112-118[Abstract/Free Full Text]
15. Diaz-Brinton R, Chen S, Montoya M, Hseih D, Minaya J, Kim J, Chu HP. The Women's Health Initiative estrogen replacement therapy is neurotrophic and neuroprotective. Neurobiol Aging 2000 21:475-496[CrossRef][Medline]
16. Brinton RD, Chen S, Montoya M, Hsieh D, Minaya J. The estrogen replacement therapy of the Women's Health Initiative promotes the cellular mechanisms of memory and neuronal survival in neurons vulnerable to Alzheimer's disease. Maturitas 2000 34:suppl 2S35-S52
17. Rossberg MI, Murphy SJ, Traystman RJ, Hurn PD. LY353381.HCl, a selective estrogen receptor modulator, and experimental stroke. Stroke 2000 31:3041-3046[Abstract/Free Full Text]
18. Kimelberg HK, Feustel PJ, Jin Y, Paquette J, Boulos A, Keller RW Jr, Tranmer BI. Acute treatment with tamoxifen reduces ischemic damage following middle cerebral artery occlusion. Neuroreport 2000 11:2675-2679[Medline]
19. Mehta SH, Dhandapani KM, Webb RC, Mahesh VB, Brann DW. Therapeutic doses of tamoxifen exert neuroprotective effects in acute ischemic stroke. Soc Neurosci Abstr 2001 27:437.11
20. Osuka K, Feustel PJ, Mongin AA, Tranmer BI, Kimelberg HK. Tamoxifen inhibits nitrotyrosine formation after reversible middle cerebral artery occlusion in the rat. J Neurochem 2001 76:1842-1850[CrossRef][Medline]
21. Obata T, Kubota S. Protective effect of tamoxifen on 1-methyl-4-phenylpyridine-induced hydroxyl radical generation in the rat striatum. Neurosci Lett 2001 308:87-90[CrossRef][Medline]
22. Silva I, Mello LE, Freymuller E, Haidar MA, Baracat EC. Estrogen, progestogen, and tamoxifen increase synaptic density of the hippocampus of ovariectomized rats. Neurosci Lett 2000 291:183-186[CrossRef][Medline]
23. Nilsen J, Mor G, Naftolin F. Raloxifene induces neurite outgrowth in estrogen receptor positive PC12 cells. Menopause 1998 5:211-216[Medline]
24. Singer CA, Rogers KL, Strickland TM, Dorsa DM. Estrogen protects primary cortical neurons from glutamate toxicity. Neurosci Lett 1996 212:13-16[CrossRef][Medline]
25. Wilson ME, Dubal DB, Wise PM. Estradiol protects against injury-induced cell death in cortical explant cultures: a role for estrogen receptors. Brain Res 2000 873:235-242[CrossRef][Medline]
26. Dubal DB, Shughrue PJ, Wilson ME, Merchenthaler I, Wise PM. Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors. J Neurosci 1999 19:6385-6393[Abstract/Free Full Text]
27. Singer CA, Rogers KL, Dorsa DM. Modulation of Bcl-2 expression: a potential component of estrogen protection in NT2 neurons. Neuroreport 1998 9:2565-2568[Medline]
28. Alkayed NJ, Goto S, Sugo N, Joh HD, Klaus J, Crain BJ, Bernard O, Traystman RJ, Hurn PD. Estrogen and Bcl-2: gene induction and effect of transgene in experimental stroke. J Neurosci 2001 21:7543-7550[Abstract/Free Full Text]
29. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A 1996 93:5925-5930[Abstract/Free Full Text]
30. Treuter E, Warner M, Gustafsson JA. Mechanism of oestrogen signalling with particular reference to the role of ER beta in the central nervous system. Novartis Found Symp 2000 230:7-14[Medline]
31. Dubal DB, Zhu H, Yu J, Rau SW, Shughrue PJ, Merchenthaler I, Kindy MS, Wise PM. Estrogen receptor alpha, not beta, is a critical link in estradiol-mediated protection against brain injury. Proc Natl Acad Sci U S A 2001 98:1952-1957[Abstract/Free Full Text]
32. Sampei K, Goto S, Alkayed NJ, Crain BJ, Korach KS, Traystman RJ, Demas GE, Nelson RJ, Hurd PD. Stroke in estrogen receptor--deficient mice. Stroke 2000 31:738-744[Abstract/Free Full Text]
33. Couse JF, Curtis SW, Washburn TF, Lindzey J, Golding TS, Lubahn DB, Smithies O, Korach KS. Analysis of transcription and estrogen insensitivity in the female mouse after targeted disruption of the estrogen receptor gene. Mol Endocrinol 1995 9:1441-1454[Abstract]
34. Wang L, Andersson S, Warner M, Gustafsson JA. Morphological abnormalities in the brains of estrogen receptor beta knockout mice. Proc Natl Acad Sci U S A 2001 98:2792-2796[Abstract/Free Full Text]
35. Kuroki Y, Fukushima K, Kanda Y, Mizuno K, Watanabe Y. Neuroprotection by estrogen via extracellular signal-regulated kinase against quinolinic acid-induced cell death in the rat hippocampus. Eur J Neurosci 2001 13:472-476[CrossRef][Medline]
36. Han BH, Holtzman DM. BDNF protects the neonatal brain from hypoxia-ischemia injury in vivo via the ERK pathway. J Neurosci 2000 20:5775-5781[Abstract/Free Full Text]
37. Philpott KL, McCarthy MJ, Klippel A, Rubin LL. Activated phosphatidylinositol 3-kinase and Akt kinase promote survival or superior cervical neurons. J Cell Biol 1997 139:809-815[Abstract/Free Full Text]
38. Eves EM, Xiong W, Bellacosa A, Kennedy SG, Tsichlis PN, Rosner MR, Hay N. Akt, a target of phosphatidylinositol 3-kinase, inhibits apoptosis in a differentiating neuronal cell line. Mol Cell Biol 1998 18:2143-2152[Abstract/Free Full Text]
39. Crowder RJ, Freeman RS. Phosphatidylinositol 3-kinase and Akt protein kinase are necessary and sufficient for the survival of nerve growth factor-dependent sympathetic neurons. J Neurosci 1998 18:2933-2943[Abstract/Free Full Text]
40. Singer CA, Figueroa-Masot XA, Batchelor RH, Dorsa DM. The mitogen-activated protein kinase pathway mediates estrogen neuroprotection after glutamate toxicity in primary cortical neurons. J Neurosci 1999 19:2455-2463[Abstract/Free Full Text]
41. Singh M, Setalo G Jr, Guan X, Warren M, Toran-Allerand CD. Estrogen-induced activation of mitogen-activated protein kinase in cerebral cortical explants: convergence of estrogen and neurotrophin signaling pathways. J Neurosci 1999 19:1179-1186[Abstract/Free Full Text]
42. Singh M, Setalo G Jr, Guan X, Frail DE, Toran-Allerand CD. Estrogen-induced activation of the mitogen-activation protein kinase cascade in the cerebral cortex of estrogen receptor- knock-out mice. J Neurosci 2000 20:1694-1700[Abstract/Free Full Text]
43. Singh M. Ovarian hormones elicit phosphorylation of Akt and extracellular signal regulated kinase in explants of the cerebral cortex. Endocrine 2001 14:407-415[CrossRef][Medline]
44. Bi R, Broutman G, Foy MR, Thompson RF, Baudry M. The tyrosine kinase and mitogen-activated protein kinase pathways mediate multiple effects of estrogen in hippocampus. Proc Natl Acad Sci U S A 2000 97:3602-3607[Abstract/Free Full Text]
45. Bi R, Foy MR, Vouimba RM, Thompson RF, Baudry M. Cyclic changes in estradiol regulate synaptic plasticity through the MAP kinase pathway. Proc Natl Acad Sci U S A 2001 98:13391-13395[Abstract/Free Full Text]
46. Brunet A, Datta SR, Greenberg ME. Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol 2001 11:297-305[CrossRef][Medline]
47. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997 91:231-241[CrossRef][Medline]
48. Cross Da, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995 378:785-789[CrossRef][Medline]
49. Honda K, Sawada H, Kihara T, Urushitani M, Nakamizo T, Akaike A, Shimohama S. Phosphatidylinositol 3-kinase mediates neuroprotection by estrogen in cultured cortical neurons. J Neurosci Res 2000 60:321-327[CrossRef][Medline]
50. Honda K, Shimohama S, Sawada H, Kihara T, Nakamizo T, Shibasaki H, Akaike A. Nongenomic antiapoptotic signal transduction by estrogen in cultured cortical neurons. J Neurosci Res 2001 64:466-475[CrossRef][Medline]
51. Zhang L, Rubinow DR, Xaing G, Li BS, Chang YH, Maric D, Barker JL, Ma W. Estrogen protects against beta-amyloid-induced neurotoxicity in rat hippocampal neurons by activation of Akt. Neuroreport 2001 12:1919-1923[CrossRef][Medline]
52. Hisamoto K, Ohmichi M, Kanda Y, Adachi K, Nishio Y, Hayakawa J, Mabuchi S, Takahashi K, Tasaka K, Miyamoto Y, Taniguchi N, Murata Y. Induction of endothelial nitric-oxide synthase phosphorylation by the raloxifene analog LY117018 is differentially mediated by Akt and extracellular signal-regulated protein kinase in vascular endothelial cells. J Biol Chem 2001 276:47642-47649[Abstract/Free Full Text]
53. Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000 407:538-541[CrossRef][Medline]
54. Kim HP, Lee JY, Jeong JK, Bae SW, Lee HK, Jo I. Nongenomic stimulation of nitric oxide release by estrogen is mediated by estrogen receptor alpha localized in caveolae. Biochem Biophys Res Commun 1999 263:257-262[CrossRef][Medline]
55. Monje P, Zanello S, Holick M, Boland R. Differential cellular localization of estrogen receptor alpha in uterine and mammary cells. Mol Cell Endocrinol 2001 181:117-129[CrossRef][Medline]
56. Moosmann B, Behl C. The antioxidant neuroprotective effect of estrogens and phenolic compounds are independent from their estrogenic properties. Proc Natl Acad Sci U S A 1999 96:8867-8872[Abstract/Free Full Text]
57. Behl C, Widmann M, Trapp T, Holsboer F. 17ß-Estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem Biophys Res Commun 1995 216:473-482[CrossRef][Medline]
58. Behl C, Skutella T, Lezoualc'h F, Post A, Widmann M, Newton CJ, Holsboer F. Neuroprotection against oxidative stress by estrogen: structure-activity relationship. Mol Pharmacol 1997 51:535-541[Abstract/Free Full Text]
59. Blum-Degen D, Haas M, Pohli S, Harth R, Romer W, Oettel M, Riederer P, Gotz ME. Scavestrogens protect IMR 32 cells from oxidative stress-induced cell death. Toxicol Appl Pharmacol 1998 152:49-55[CrossRef][Medline]
60. Goodman Y, Bruce AJ, Cheng B, Mattson MP. Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid ß-peptide toxicity in hippocampal neurons. J Neurochem 1996 66:1836-1844[Medline]
61. Bae YH, Hwang JY, Kim YH, Koh JY. Anti-oxidative neuroprotection by estrogens in mouse cortical cultures. J Korean Med Sci 2000 15:327-336[Medline]
62. Green PS, Gridley KE, Simpkins JW. Estradiol protects ß-amyloid (25–35)-induced toxicity in SK-N-SH human neuroblastoma cells. Neurosci Lett 1996 218:165-168[CrossRef][Medline]
63. Mook-Jung I, Joo I, Sohn S, Kwon HJ, Huh K, Jung MW. Estrogen blocks neurotoxic effects of beta-amyloid (1–42) and induces neurite extension on B103 cells. Neurosci Lett 1997 235:101-104[CrossRef][Medline]
64. Lacort M, Leal AM, Liza M, Martin C, Martinez R, Ruiz-Larrea B. Protective effect of estrogens and catecholestrogens against peroxidative membrane damage in vitro. Lipids 1995 30:141-146[Medline]
65. Vedder H, Anthes N, Stumm G, Wurz C, Behl C, Krieg JC. Estrogen hormones reduce lipid peroxidation in cells and tissues of the central nervous system. J Neurochem 1999 72:2531-2538[CrossRef][Medline]
66. Cardona-Gomez GP, Mendez P, DonCarlos LL, Azcoitia I, Garcia-Segura LM. Interactions of estrogens and insulin-like growth factor-I in the brain: implications for neuroprotection. Brain Res Rev 2001 37:320-334[CrossRef][Medline]
67. Cui W, Allen ND, Skynner M, Gusterson B, Clark AJ. Inducible ablation of astrocytes shows that these cells are required for neuronal survival in the adult brain. Glia 2001 34:272-282[CrossRef][Medline]
68. Dhandapani KM, Wade FM, Buchanan CD, Brann DW. Transforming growth factor-ß released by astrocytes enhances connectivity and survival of neurons: regulation by 17ß-estradiol. In: Program of the annual meeting of the American Society for Cell Biology; 2000; San Francisco, CA. Abstract 141
69. D'Onofrio M, Cuomo L, Battaglia G, Ngomba RT, Storto M, Kingston AE, Orzi F, De Blasi A, Di Iorio O, Nicoletti F, Bruno V. Neuroprotection mediated by glial group-II metabotropic glutamate receptors requires the activation of the MAP kinase and the phosphatidylinositol-3-kinase pathways. J Neurochem 2001 78:435-445[CrossRef][Medline]
70. Wang XF, Cynader MS. Pyruvate released by astrocytes protects neurons from copper-catalyzed cysteine neurotoxicity. J Neurosci 2001 21:3322-3331[Abstract/Free Full Text]
71. Lamigeon C, Bellier JP, Sacchettoni S, Rujano M, Jacquemont B. Enhanced neuronal protection from oxidative stress by coculture with glutamic acid decarboxylase-expressing astrocytes. J Neurochem 2001 77:598-606[CrossRef][Medline]
72. Hosli E, Ruhl W, Hosli L. Histochemical and electrophysiological evidence for estrogen receptors on cultured astrocytes: colocalized with cholinergic receptors. Int J Dev Neurosci 2000 18:101-111[CrossRef][Medline]
73. Hosli E, Jurasin K, Ruhl W, Luthy R, Hosli L. Colocalization of androgen, estrogen, and cholinergic receptors on cultured astrocytes of rat central nervous system. Int J Dev Neurosci 2001 19:11-19[CrossRef][Medline]
74. Buchanan CD, Mahesh VB, Brann DW. Estrogen-astrocyte-luteinizing hormone-releasing hormone signaling: a role for transforming growth factor-beta 1. Biol Reprod 2000 62:1710-1721[Abstract/Free Full Text]
75. Azcoitia I, Sierra A, Garcia-Segura LM. Localization of estrogen receptor-ß immunoreactivity in astrocytes of the adult rat brain. Glia 1999 26:260-267[CrossRef][Medline]
76. Santagati S, Melcangi RC, Celotti F, Martini L, Maggi A. Estrogen receptor is expressed in different types of glial cells in culture. J Neurochem 1994 63:2058-2064[Medline]
77. Bruno V, Battaglia G, Casabona G, Copani A, Caciagli F, Nicoletti F. Neuroprotection by glial metabotropic glutamate receptors is mediated by transforming growth factor-beta. J Neurosci 1998 18:9594-9600[Abstract/Free Full Text]
78. Prehn JH, Bindokas VP, Marcuccilli CJ, Krajewski S, Reed JC, Miller RJ. Regulation of neuronal Bcl-2 protein expression and calcium homeostasis by transforming growth factor beta confers wide-ranging protection on rat hippocampal neurons. Proc Natl Acad Sci U S A 1994 91:12599-12603[Abstract/Free Full Text]
79. Prehn JH, Bindokas VP, Jordan J, Galindo MF, Ghadge GD, Roos RP, Boise LH, Thompson CB, Krajewski S, Reed JC, Miller RJ. Protective effect of transforming growth factor beta1 on beta-amyloid neurotoxicity in rat hippocampal neurons. Mol Pharmacol 1996 49:319-328[Abstract]
80. Ren RF, Flanders KC. Transforming growth factor beta protects primary rat hippocampal neuronal cultures from degeneration induced by beta-amyloid peptide. Brain Res 1996 732:16-24[CrossRef][Medline]
81. Ren RF, Hawver DB, Kim RS, Flanders KC. Transforming growth factor beta protects human hNT cells from degeneration induced by beta-amyloid peptide: involvement of the TGF-beta type II receptor. Brain Res Mol Brain Res 1997 48:315-322[Medline]

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