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Experimental Biology and Medicine 231:514-521 (2006)
© 2006 Society for Experimental Biology and Medicine

MINIREVIEW

Novel Mechanisms for Estrogen-Induced Neuroprotection

Meharvan Singh*,1, James A. Dykens{dagger} and James W. Simpkins*

* Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107; and {dagger} EyeCyte Therapeutics, San Diego, California 92024

1 To whom requests for reprints should be addressed at Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107. E-mail: msingh{at}hsc.unt.edu


   Abstract
Top
 Abstract
Introduction
 Mechanisms of Action
 References
 
Estrogens are gonadal steroid hormones that are present in the circulation of both males and females and that can no longer be considered within the strict confines of reproductive function. In fact, the bone, the cardiovascular system, and extrahypothalamic regions of the brain are now well-established targets of estrogens. Among the numerous aspects of brain function regulated by estrogens are their effects on mood, cognitive function, and neuronal viability. Here, we review the supporting evidence for estrogens as neuroprotective agents and summarize the various mechanisms that may be involved in this effect, focusing particularly on the mitochondria as an important target. On the basis of this evidence, we discuss the clinical applicability of estrogens in treating various age-related disorders, including Alzheimer disease and stroke, and identify the caveats that must be considered.

Key Words: estrogen • estradiol • neuroprotection • cytoprotection • mitochondria • signaling pathways


   Introduction
Top
 Abstract
 Introduction
Mechanisms of Action
 References
 
Estrogens are gonadal steroid hormones that have classically been associated with reproductive function and, with respect to the brain, have primarily been considered within the confines of the hypothalamus. However, it is now well recognized that estrogens affect numerous extrahypothalamic regions of the brain, the consequence of which is to regulate such important functions as mood and cognitive function. In addition, a substantive and growing body of literature supports the neuroprotective actions of estrogens, which have been shown to be effective at protecting against cellular dysfunction and/or damage. For example, in vitro and in vivo studies have described estrogen’s protective effects against such insults as serum deprivation (1–3), amyloid ß peptide (Aß)–induced toxicity (4–7), glutamate-induced excitotoxicity (6, 8, 9), hydrogen peroxide (H2O2) (4, 6, 7), oxygen-glucose deprivation (OGD) (10, 11), iron toxicity (6, 12), hemoglobin (10), and mitochondria toxins such as 3-NPA (13), N-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) (14), and sodium azide (10). The neuroprotective effects of estrogens have also been demonstrated in a variety of models of acute cerebral ischemia. These include transient and permanent middle cerebral artery occlusion models (15–17), global forebrain ischemia models (18, 19), photothrombotic focal ischemia models (20), and glutamate-induced focal cerebral ischemia models (21). The protective effects of estrogens have been described in rats, mice, and gerbils (22, 23). Estrogen-induced neuroprotection has been demonstrated in adult female rats, middle-aged female rats, and reproductively senescent female rats (24). Similarly, these effects of estrogens have been shown despite the presence of diabetes and hypertension (25, 26). The neuroprotective effects of estrogens have been demonstrated against subarachnoid hemorrhage, a highly prevalent form of stroke in females (27). Finally, the neuroprotective action of estrogen is not limited to the female, inasmuch as estrogen protection is also seen in males (28, 29). Collectively, these results indicate that estrogens could be valuable candidates for brain protection in both males and females. We describe the major mechanisms and cellular/subcellular targets of estrogen that mediate these protective effects.


   Mechanisms of Action
Top
 Abstract
 Introduction
 Mechanisms of Action
References
 
Estrogen Receptors.
Three major forms of estrogen exist in humans and rodents: the biologically most prevalent and potent estrogen 17ß-estradiol (E2) and, in order of decreasing potency, estrone (E1) and estriol (E3). These estrogens are known to exert their actions through members of the nuclear hormone receptor superfamily, estrogen receptor-{alpha} (ER-{alpha}) (30), and the more recently identified estrogen receptor-ß (ER-ß) (31–33). Estrogen binding to these receptors promotes receptor dimerization and translocation to the nucleus, where subsequent association of "activated" receptor with specific DNA sequences in the promoter region of target genes (34) leads to the regulation of transcription (35). These receptors differ in their affinities for ligand, specificities for ligands (36), and tissue distribution (36, 37). Given the overlap in expression, such as the coexpression of both ER-{alpha} and ER-ß mRNA in the cerebral cortex and hippocampus (37–40), studies have been performed to ascertain which receptor underlies the neuroprotective effects of estrogen.

In cell-culture systems that express, either naturally or experimentally, one of the two known estrogen receptors (ER-{alpha} or ER-ß), pharmacological strategies that use estrogen-receptor antagonists, such as tamoxifen and ICI 182,780, have supported the requirement of these receptors in mediating the effects of estrogen on cell survival (41, 42). Some studies support the role of ER-{alpha} (43), whereas others implicate ER-ß in mediating estrogen-induced protection (44). In vivo studies have also been performed to address the role of these estrogen receptors in mediating neuroprotection. For example, Dubal et al. (16) reported that the protective effects of low-dose estrogen (resulting in plasma levels that are approximately 25 pg/ml) against experimentally-induced stroke were abolished in ER-{alpha} knockout (ER{alpha}KO) mice. However, ER{alpha}KO mice are exposed to much higher levels of estrogen than their wild-type counterparts (45), likely because of the absence of negative feedback at the level of the hypothalamus. As such, the "threshold" for the protective effects of estrogen may have been much higher. Consistent with this idea, administration of higher concentrations of estradiol (approximately 200 pg/ ml) to ER{alpha}KO mice was effective at reducing infarct volume (46, 47). Thus, depending on the region of the brain, either ER-{alpha} or ER-ß may be involved in mediating estrogen’s protective effects. An added complexity results from the observation that ER-{alpha} and ER-ß can exist and act not only as homodimers, but also as heterodimers (32, 48, 49), which suggests a functional interaction between ER-{alpha} and ER-ß. Thus, an "appropriate" balance between the levels of ER-{alpha} and ER-ß may be required to mediate estrogen-induced neuroprotection, and alterations in the ratio between these receptors may determine whether estrogen is protective or damage promoting (as has been seen in reproductively senescent animals [50, 51]).

Identification of the receptor(s) that mediate the protective effects of estrogen have been complicated by the suggestion that there are membrane-associated estrogen receptors (52–55). On the one hand, it has been suggested that these membrane receptors are simply subpopulations of ER-{alpha} and/or ER-ß, but other investigators have argued that the membrane estrogen receptor represents a completely distinct and novel class of estrogen receptor (56). However, the extent to which these membrane receptors are involved in mediating estrogen-induced neuroprotection is still unclear and will undoubtedly be clarified with further research and eventual cloning of potentially new estrogen receptors.

Regulation of Signal Transduction Pathways.
The classical mechanism of hormone action states that, because of their lipophilicity, estrogens cross the plasma membrane to bind to intracellular estrogen receptors, resulting in translocation of the activated estrogen receptor into the nucleus and eventual regulation of gene transcription. However, this "genomic" mechanism of action is insufficient to explain the broad scope of estrogen’s actions, including the rapidity of some of estrogen’s actions in the brain. Alternate mechanisms have indeed been recognized, including the regulation of signal transduction pathways typically associated with growth-factor action. These include, but are not limited to, the reported ability of estrogen to elicit the Ras/Raf/ERK(MAPK) pathway (57–60), the PI-3K/Akt pathway (59, 61–63), and the cAMP/ PKA/CREB pathway (63, 64) and to modulate the NF{kappa}B pathways (65, 66). These pathways have all been linked to the regulation of cell survival, although the importance of one or more of these pathways in mediating the protective effects of estrogen may be cell or context dependent. The activation of these signaling pathways in response to estrogen has been reviewed in greater detail by us and others previously (67–69). In the following sections, we highlight the mitochondria as important mechanistic targets for estrogen-induced neuroprotection.

Mitochondria and Neurodegenerative Diseases.
Mitochondria are subcellular organelles that serve not only as the primary source for cellular energy, but are also the major source of intracellular free radicals. Thus, mitochondria supply high-energy ATP molecules and monitor cellular health, and they sit at a strategic position in the hierarchy of cellular organelles to make cell decisions regarding the survival or death of cells (70, 71). These mitochondrial roles are critical in the brain, given its high energy demand that is driven by the need to maintain ion gradients across the plasma membrane, which, in turn, is critical for the generation of action potentials. Although the brain represents only 2% of the body weight, it receives 15% of cardiac output and uses 20% of total body oxygen. This intense energy requirement is continuous and implies that even brief periods of oxygen or glucose deprivation can result in neuronal death.

Among the factors underlying the degeneration of neurons in such neurodegenerative diseases as Alzheimer’s disease (AD) is the generation of excessive amounts of reactive oxygen species (ROS) (72, 73). In fact, mitochondria from patients with AD are hypofunctional (74, 75) because of a catalytic defect in respiratory complex IV (C-IV) of AD-associated mitochondria (76, 77). Furthermore, when mitochondrial DNA (mtDNA) from patients with AD were inserted into transformed cells depleted of their endogenous mtDNA, the resulting phenotype included the formation of cytoplasmic hybrids (cybrids), increased oxidative stress, propensity towards apoptosis, and C-IV impairment (78, 79), suggesting that many of the cellular defects found in association with AD reflect mitochondrial defects. Although such mitochondrial impairment could be interpreted as a consequence of the disease, rather than as a primary causal factor (80), mitochondrial dysfunction is clearly involved in the progression of neuronal death and, as such, represents a viable therapeutic target.

Mitochondrial failure also contributes to cell death in more-acute circumstances, such as sudden ischemia of neurons during a stroke or of the myocardium during a heart attack. Neurons are dependent almost entirely on mitochondrial ATP production for their high energy demand, and are at risk when ATP levels drop, even transiently. Damage to mitochondria causes disruptions in ATP production and a concomitant increase in ROS that can overwhelm the antioxidant defense systems of the cell (71, 81). Such mitochondrial deficits are implicated as key events in the pathogenic cascades leading to both necrosis and apoptosis (82, 83). Oxidative stress, coupled with excessive Ca2+ loading, causes mitochondria to undergo a catastrophic loss of the inner mitochondrial membrane integrity, leading to an eventual collapse of the mitochondrial membrane potential ({Delta}{Psi}m), a process called permeability transition (PT) (70). This collapse of {Delta}{Psi}m can be accompanied by mitochondrial swelling and release of cytochrome c and Apaf-1 (84) into the cytoplasm, leading, in turn, to the activation of caspases and apoptotic cell death (81, 83, 85, 86). This process undermines cellular and mitochondrial integrity by causing membrane peroxidation and interfering with oxidative phosphorylation. The resulting loss of ATP production causes ATPase failure, loss of ion homeostasis, and necrosis due to osmotic failure (71, 85).

Mitochondria as a Target of Estrogen-Induced Neuroprotection.
The possibility that estrogens exert their potent neuroprotective effects through a mitochondrial mechanism is based on several observations. These effects may be exerted either directly or indirectly. Indirect effects of estrogen on the mitochondria may be mediated by signal transduction pathways that are not only elicited by estrogens, but are also important regulators of mitochondrial function. For example, estrogen can elicit the activation of the PI-3K/Akt pathway (59, 61–63), which, in turn, can result in the phosphorylation of the proapoptotic protein BAD. When phosphorylated, BAD is rendered inactive and prevents BAX-mediated release of cytochrome c from the mitochondria (87). Further, estrogens have been shown to affect concentrations and localization of antiapoptotic proteins (88–90), which appear to exert their antiapoptotic effects through maintenance of mitochondrial membrane potential in the face of cellular stresses (91).

Although mitochondria can be protected via indirect mechanisms (i.e., through regulation of signal transduction pathways or mobilization of antiapoptotic proteins), estrogen may also exert its protective actions directly. Supporting evidence comes from the observation of estrogen binding sites in the mitochondria, including the F0/F1 ATPase (92, 93). In fact, we showed that ER-ß localizes to the mitochondria (90). Importantly, we have demonstrated that estrogens, after insults that are known to compromise the function of the mitochondria, are protective and help maintain the normal function of this vital organelle (13, 94). These findings are summarized as follows.

By use of oxidative stress–inducing mitochondrial toxins (13) or H2O2 (94), 17ß-estradiol (E2) pretreatment ameliorated the insult-induced decrease in cellular ATP. One possible mechanism for these effects is that estrogens are potent lipid peroxidation inhibitors (94). Estrogens are highly lipid soluble and largely reside in the membrane component of cells (95, 96), where they are ideally suited to affect oxidation of unsaturated bonds in phospholipids. This membrane localization allows estrogens to interact synergistically with such abundant antioxidants as glutathione (97, 98), where they can apply their cytosolic reducing potential to the membrane (99). In fact, we provided evidence that estrogen prevents lipid peroxidation by sacrificing itself to oxidation, resulting in a quinol product. Interestingly, the oxidized estrogen was redox-cycled back to the parent estrogen by taking advantage of the plentiful and replenishable source of cellular reducing potential, such as glutathione or NAD(P)H (100, 101). This estrogen redox cycle is operative in the brain and serves, together with the "classic" antioxidant mechanism (102), as a defense mechanism against ROS.

Estrogens can also affect mitochondrial function by directly or indirectly influencing mitochondrial Ca2+ loading. Brinton et al. (88, 103) demonstrated that, with mild glutamate stimulation, estrogens enhance Ca2+ flux into cells, and this effect may be involved in estrogen’s ability to increase memory function through an N-methyl-D-aspartate (NMDA)-mediated mechanism (104–106). With excitotoxic stimulation (as with high glutamate concentrations) (88, 103) or pro-oxidant stimulation (13, 94), however, estrogens prevented both cytosolic and mitochondrial influx of Ca2+, thus providing a protection against excessive Ca2+ influx.

As stated above, {Delta}{Psi}m collapse is a critical event in promoting the death of neurons (83, 84, 107, 108). In fact, two methods of analysis revealed the protective effects of E2 against mitochondrial toxin–induced collapse of {Delta}{Psi}m in neuronal cultures. First, using rhodamine 123 (a mitochondria-specific dye), we demonstrated that pretreatment of neurons with E2 prevented mitochondrial toxin–induced mitochondrial depolarization (13). Similarly, using a fluorescence resonance energy transfer (FRET) assay to measure {Delta}{Psi}m (109), we observed that treatment with either E2 or its diastereomer 17 {alpha}-estradiol (17 {alpha}-E2) resulted in a condition in which increased Ca2+ concentrations were required to cause {Delta}{Psi}m collapse (99). Collectively, these data indicated that estrogens protect mitochondria by preventing {Delta}{Psi}m collapse and could explain the ability of estrogens to prevent the release of apoptotic factors from the mitochondria (70), which is dependent on {Delta}{Psi}m collapse.

Clinical Implications of Estrogen Neuroprotection.
Epidemiological studies have shown that estrogen therapy (ET) administered soon after the menopause is associated with numerous health benefits, including a reduction in the risk for cardiovascular diseases (110), decreased incidence of osteoporosis and associated bone fractures (111), decreased risk for neurodegenerative diseases (112), increased cognitive performance (113), and reduced risk for cataract (114). With respect to AD, there have been several clinical and epidemiological studies that describe estrogen’s beneficial effects. For example, the seminal study by Fillit et al. (115) described a cognitive improvement in patients with AD who received estrogen treatment for 6 weeks. Since that study, a growing body of literature has shown that estrogen therapy may contribute to the prevention, attenuation, or even the delay of the onset of AD (116–120). Furthermore, estrogen replacement may also facilitate other treatments used for the treatment of AD. For example, in clinical trials that used Tacrine, an anticholin-esterase drug used for the treatment of AD, a greater efficacy was seen in women receiving estrogen therapy than in women who were not (121).

Given the aforementioned evidence for the potent neuroprotective effects of a variety of estrogens in cell and animal models, as well as the epidemiological evidence of the efficacy of early postmenopausal treatment, it would seem to be reasonable that one or more of these compounds would be assessed in clinical trials for estrogens in stroke, AD, or other neurodegenerative conditions. However, the prospect of the clinical use of estrogens for neuroprotective therapy was dealt a severe blow with findings from the Women’s Health Initiative (WHI) studies, which were published beginning in 2002. These studies assessed a variety of outcome measures that followed years of continuous daily administration of two hormone preparations, Premarin (Wyeth Pharmaceuticals, Philadelphia, PA; Refs. 122, 123) and PremPro (Wyeth; Refs. 124–126). Premarin is derived from the urine of pregnant mares and contains an abundance of equine estrogens, whereas PremPro consists of Premarin and medroxyprogesterone acetate (MPA). These studies were terminated early because the risks of therapy appeared to outweigh the benefits of treatment.

Although informative, the interpretation of the WHI studies is limited by the hormone preparations used, their route of administration, the regimen of hormone administration (i.e., continuous daily therapy versus cyclic therapy), and the advanced age of the subjects under study (127, 128). It is well known that oral administration of estrogens induces prothrombotic factors (129, 130), and this has accounted for the slight increase in the risk of deep venous thrombosis, heart attack, and stroke observed among women treated with Premarin and PremPro. It has also been suggested that the subjects in the population under study, who averaged 63 years of age at the time of study entry, had "silent" cardiovascular disease (131), and that sudden exposure to estrogens exacerbated the already-existing undiagnosed vascular disease in these women.

Given that we now have extensive knowledge of the signaling pathways that mediate estrogen-induced neuroprotection (see above), the structure-activity relationships for estrogen-induced neuroprotection (1, 132), and the route of administration that minimizes the negative effects consequent to the first-pass effect (133), novel drugs and delivery methods for estrogen neuroprotection can be investigated in future clinical studies. In brief, there are safe and effective means to administer estrogens (including nonfeminizing estrogens) for the treatment of nerve cell loss associated with chronic neurodegenerative disease and more-acute nerve cell compromising conditions, such as stroke and head injury.


   Footnotes
 
Some of the studies described in this review were supported by grants from the National Institutes of Health (AG 010485 to J.W.S., AG 022550 to J.W.S. and M.S., and AG 023330 to M.S.).


   References
Top
 Abstract
 Introduction
 Mechanisms of Action
 References
 

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