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a Institute of Molecular Medicine and Genetics, Program in Neurobiology, and Department of Neurology, Medical College of Georgia, Augusta, Georgia 30912
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONEVIDENCE FOR A NEUROPROTECTIVE...EVIDENCE FOR AN ER-MEDIATED...EVIDENCE FOR A NONGENOMIC...EVIDENCE FOR AN ANTIOXIDANT...OTHER MECHANISMS?CONCLUSIONS AND FUTURE...REFERENCES |
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estradiol, neuroendocrinology, steroid hormones
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONEVIDENCE FOR A NEUROPROTECTIVE...EVIDENCE FOR AN ER-MEDIATED...EVIDENCE FOR A NONGENOMIC...EVIDENCE FOR AN ANTIOXIDANT...OTHER MECHANISMS?CONCLUSIONS AND FUTURE...REFERENCES |
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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.
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EVIDENCE FOR A NEUROPROTECTIVE ROLE FOR 17ß-E2 AND SERMs |
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TOPABSTRACTINTRODUCTIONEVIDENCE FOR A NEUROPROTECTIVE...EVIDENCE FOR AN ER-MEDIATED...EVIDENCE FOR A NONGENOMIC...EVIDENCE FOR AN ANTIOXIDANT...OTHER MECHANISMS?CONCLUSIONS AND FUTURE...REFERENCES |
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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.
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EVIDENCE FOR AN ER-MEDIATED GENOMIC ACTIVATION MECHANISM |
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TOPABSTRACTINTRODUCTIONEVIDENCE FOR A NEUROPROTECTIVE...EVIDENCE FOR AN ER-MEDIATED...EVIDENCE FOR A NONGENOMIC...EVIDENCE FOR AN ANTIOXIDANT...OTHER MECHANISMS?CONCLUSIONS AND FUTURE...REFERENCES |
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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.
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EVIDENCE FOR A NONGENOMIC MECHANISM FOR 17ß-E2 NEUROPROTECTION |
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TOPABSTRACTINTRODUCTIONEVIDENCE FOR A NEUROPROTECTIVE...EVIDENCE FOR AN ER-MEDIATED...EVIDENCE FOR A NONGENOMIC...EVIDENCE FOR AN ANTIOXIDANT...OTHER MECHANISMS?CONCLUSIONS AND FUTURE...REFERENCES |
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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]
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EVIDENCE FOR AN ANTIOXIDANT MECHANISM FOR 17ß-E2 NEUROPROTECTION |
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TOPABSTRACTINTRODUCTIONEVIDENCE FOR A NEUROPROTECTIVE...EVIDENCE FOR AN ER-MEDIATED...EVIDENCE FOR A NONGENOMIC...EVIDENCE FOR AN ANTIOXIDANT...OTHER MECHANISMS?CONCLUSIONS AND FUTURE...REFERENCES |
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-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.
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OTHER MECHANISMS? |
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TOPABSTRACTINTRODUCTIONEVIDENCE FOR A NEUROPROTECTIVE...EVIDENCE FOR AN ER-MEDIATED...EVIDENCE FOR A NONGENOMIC...EVIDENCE FOR AN ANTIOXIDANT...OTHER MECHANISMS?CONCLUSIONS AND FUTURE...REFERENCES |
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CONCLUSIONS AND FUTURE DIRECTIONS |
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TOPABSTRACTINTRODUCTIONEVIDENCE FOR A NEUROPROTECTIVE...EVIDENCE FOR AN ER-MEDIATED...EVIDENCE FOR A NONGENOMIC...EVIDENCE FOR AN ANTIOXIDANT...OTHER MECHANISMS?CONCLUSIONS AND FUTURE...REFERENCES |
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FOOTNOTES |
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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.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONEVIDENCE FOR A NEUROPROTECTIVE...EVIDENCE FOR AN ER-MEDIATED...EVIDENCE FOR A NONGENOMIC...EVIDENCE FOR AN ANTIOXIDANT...OTHER MECHANISMS?CONCLUSIONS AND FUTURE...REFERENCES |
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-deficient mice. Stroke 2000 31:738-744 knock-out mice. J Neurosci 2000 20:1694-1700This article has been cited by other articles:
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