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Reprint of: From the 90׳s to now: A brief historical perspective on more than two decades of estrogen neuroprotection
Abstract
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Historical perspective abstract:From the 90׳s to now: a historical perspective on more than two decades of estrogen neuroprotection: In the early 90׳s, estrogens were known to exert organizational and activational effects on reproductive tissues and sexual behavior. As well, the role of sex and gonadal hormones in altering the risk for developing Alzheimer׳s Disease (AD) was only beginning to be elucidated. Preliminary investigations suggested that estrogen-containing therapies typically given for the management of disruptive menopausal symptoms could reduce AD risk, attenuate disease-associated cognitive deficits, and modulate brain substrates known to be dysregulated by the condition, such as the cholingeric system. The findings from our seminal paper demonstrating cognitive benefits and cholinergic impacts with exogenous estrogen treatment in a rodent model of surgical hormone depletion provided initial support for use of estrogen-containing therapies as a treatment for age-related brain disorders. We then went on to demonstrate neuroprotective actions of estrogen in several other in vivo and in vitro models of neurological challenge, including stroke and AD. Further, our findings of the chemical structure requirements for estrogen׳s neuroprotective effects identified a novel approach for optimizing future estrogen-containing hormone therapy options. These early efforts laid the groundwork for later, large-scale clinical investigations into the potential of estrogen-based menopausal hormone therapies for the prevention of a variety of age-related disorders. Although findings of these studies were equivocal, the neuroprotective actions of estrogen, and specifically 17β-estradiol, identified by early investigations, remain well-documented. Future development of interventions that optimize cognitive aging are crucial and, with proper understanding of the factors that influence the realization of beneficial impacts, estrogen-containing treatments may still be among these.
Original article abstract:
Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague-Dawley rats: We hypothesized that estradiol (E2) serves as a neurotrophomodulatory substance for basal forebrain cholinergic neurons thought to be involved in learning and memory. Learning/memory was assessed using the two-way active avoidance paradigm and the Morris water task. Female Sprague-Dawley rats were either ovariectomized (OVX) or OVX for 3 weeks, followed by s.c. implantation of a Silastic pellet containing 17-βE2 (E2 pellet), resulting in a replacement of E2 to physiological levels. Ovary-intact (INTACT) animals served as our positive control. Active avoidance behavior and choline acetyltransferase (ChAT) activity in the frontal cortex and hippocampus were assessed at 5 and 28 weeks postovariectomy while performance on the Morris water task and high-affinity choline uptake (HACU) were measured only at the 5-week time point. At the 5-week time point, E2 replacement caused a significant elevation in the level of active avoidance performance relative to OVX animals. At the 28-week time point, OVX animals demonstrated a significantly lower number of avoidances relative to controls (61%) whereas E2-pellet animals not only demonstrated superior performance relative to OVX animals but also showed an accelerated rate of learning. Morris water task performance, on the other hand, was not significantly affected by estrogenic milieu despite a trend towards better performance in the E2-pellet group. Neurochemical analyses revealed that 5 weeks of ovariectomy was sufficient to reduce HACU in both the frontal cortex and hippocampus by 24 and 34%, respectively, while E2 replacement was successful in elevating HACU relative to OVX animals in both regions. ChAT activity was decreased in the hippocampus but not the frontal cortex of 5-week OVX animals. E2 replacement resulted in a reversal of this effect. At the 28-week time period, an unexpected decrease in ChAT activity was observed across all treatment groups. Interestingly, E2-pellet animals demonstrated the least severe decline in ChAT. This phenomenon was most evident in the frontal cortex where ChAT decreased by 61 and 56% in INTACT and OVX animals, respectively, whereas the decline in E2-pellet animals was only 16% over the same time period, suggesting a previously unreported cytoprotective effect of E2. Taken together, these findings demonstrate important effects of estrogens on cholinergic neurons and support the potential use of estrogen therapy in treatment of dementias in postmenopausal women. © 1994. This article is part of a Special Issue entitled SI:50th Anniversary Issue.
... Furthermore, they influence synaptic formation through various signaling pathways and play critical roles in neuroprotection [9,10,12]. Rodent studies demonstrate ovariectomized rats had decreased dendritic spine density of neurons in the hippocampus and prefrontal cortex [13], with increased spinal density in these areas after exogenous estradiol administration [14,15]. Such studies also demonstrated an estrogen-enhanced correlation with performance on memory tasks [13,15]. ...
... Rodent studies demonstrate ovariectomized rats had decreased dendritic spine density of neurons in the hippocampus and prefrontal cortex [13], with increased spinal density in these areas after exogenous estradiol administration [14,15]. Such studies also demonstrated an estrogen-enhanced correlation with performance on memory tasks [13,15]. Progesterone has been studied less extensively. ...
Sex hormones, such as estrogens, progesterone, and testosterone, have a significant influence on brain, behavior, and cognitive functioning. The menstrual cycle has been a convenient model to examine how subtle fluctuations of these hormones can relate to emotional and cognitive functioning. The aim of the current paper is to provide a narrative review of studies investigating cognitive functioning in association with the menstrual cycle in biological females, with a focus on studies that have investigated cognitive functioning across the menstrual cycle in females with premenstrual mood disorders, such as premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). In line with previous reviews, the current review concluded that there is a lack of consistent findings regarding cognitive functioning across the menstrual cycle. Most studies focused on changes in levels of blood estrogen, and neglected to explore the role of other hormones, such as progesterone, on cognitive functioning. Cognitive research involving premenstrual disorders is in its infancy, and it remains unclear whether any cognitive disturbances that are identified may be attributed to negative experience of mood and psychological symptoms or be a more direct effect of hormonal dysregulation or sensitivity. Suggestions for future research are provided.
... Deficiency of 17-β-estradiol (E2), a major form of estrogens, is implicated in age-related cognitive decline in human and non-human primates. Estrogens modulate hippocampal synaptic spine growth, structural plasticity, and neuronal excitability, which affect long-term potentiation in learning and memory (Teyler et al., 1980;Brinton, 1993;Warren et al., 1995;Engler-Chiurazzi et al., 2016;Muñoz-Mayorga et al., 2018). ...
... Decreased serum sex steroid hormone levels in postmenopausal women or in aged men increase the risk for developing NDs. Participation of steroid sex hormones in neuroprotection through the interaction of E2 and estrogen receptors (ER) during brain injury and neurodegeneration has been extensively investigated and very well reviewed (Brann et al., 2007;Arevalo et al., 2015;Engler-Chiurazzi et al., 2016). ...
Homozygous null mutation of tumor suppressor WWOX/Wwox gene leads to severe neural diseases, metabolic disorders and early death in the newborns of humans, mice and rats. WWOX is frequently downregulated in the hippocampi of patients with Alzheimer’s disease (AD). In vitro analysis revealed that knockdown of WWOX protein in neuroblastoma cells results in aggregation of TRAPPC6AΔ, TIAF1, amyloid β, and Tau in a sequential manner. Indeed, TRAPPC6AΔ and TIAF1, but not tau and amyloid β, aggregates are present in the brains of healthy mid-aged individuals. It is reasonable to assume that very slow activation of a protein aggregation cascade starts sequentially with TRAPPC6AΔ and TIAF1 aggregation at mid-ages, then caspase activation and APP de-phosphorylation and degradation, and final accumulation of amyloid β and Tau aggregates in the brains at greater than 70 years old. WWOX binds Tau-hyperphosphorylating enzymes (e.g., GSK-3β) and blocks their functions, thereby supporting neuronal survival and differentiation. As a neuronal protective hormone, 17β-estradiol (E2) binds WWOX at an NSYK motif in the C-terminal SDR (short-chain alcohol dehydrogenase/reductase) domain. In this review, we discuss how WWOX and E2 block protein aggregation during neurodegeneration, and how a 31-amino-acid zinc finger-like Zfra peptide restores memory loss in mice.
... Based on these findings, it is suggested that the effects of ADE 2 in enhancing reactive astrogliosis and restraining microglia activation after a GCI may contribute to its neuroprotective effects in the brain following an ischemic injury. The direct protective effects of ADE 2 on neurons could also contribute to its neuroprotective actions, as hippocampal neurons express all three estrogen receptor subtypes [41,42] and the direct protective effects of E 2 on neurons in vitro has been demonstrated in many studies [43,44]. ...
17β-estradiol (E2) is produced in the brain as a neurosteroid, in addition to being an endocrine signal in the periphery. The current animal models for studying brain-derived E2 include global and conditional non-inducible knockout mouse models. The aim of this study was to develop a tamoxifen (TMX)-inducible astrocyte-specific aromatase knockout mouse line (GFAP-ARO-iKO mice) to specifically deplete the E2 synthesis enzymes and aromatase in astrocytes after their development in adult mice. The characterization of the GFAP-ARO-iKO mice revealed a specific and robust depletion in the aromatase expressions of their astrocytes and a significant decrease in their hippocampal E2 levels after a GCI. The GFAP-ARO-iKO animals were alive and fertile and had a normal general brain anatomy, with a normal astrocyte shape, intensity, and distribution. In the hippocampus, after a GCI, the GFAP-ARO-iKO animals showed a major deficiency in their reactive astrogliosis, a dramatically increased neuronal loss, and increased microglial activation. These findings indicate that astrocyte-derived E2 (ADE2) regulates the ischemic induction of reactive astrogliosis and microglial activation and is neuroprotective in the ischemic brain. The GFAP-ARO-iKO mouse models thus provide an important new model to help elucidate the roles and functions of ADE2 in the brain.
... A study has shown that 17β-estradiol can act directly or indirectly on the palindromic estrogenresponsive region of the telomerase catalytic subunit hTERT (human telomerase reserve transcriptase gene) promoter, suggesting that estrogen may affect cellular senescence through the up-regulation of telomerase activity, the enzyme that regulates the telomere stability (Kyo et al. 1999). This was further supported by another study that the length of leukocyte telomeres was significantly higher in postmenopausal women after long-term oral administration of conventional doses of estrogen than in unmedicated menopausal women (Engler-Chiurazzi et al. 2016). Estrogen was found regulating s telomerase activity by extending telomere length and reducing telomere depletion and be reducing thus protecting chromosome integrity which subsequently slows cellular senescence. ...
Atherosclerosis threatens human health by developing cardiovascular diseases, the deadliest disease world widely. The major mechanism contributing to the formation of atherosclerosis is mainly due to vascular endothelial cell (VECs) senescence. We have shown that 17β-estradiol (17β-E2) may protect VECs from senescence by upregulating autophagy. However, little is known about how 17β-E2 activates the autophagy pathway to alleviate cellular senescence. Therefore, the aim of this study is to determine the role of estrogen receptor (ER) α and β in the effects of 17β-E2 on vascular autophagy and aging through in vitro and in vivo models. Hydrogen peroxide (H2O2) was used to establish Human Umbilical Vein Endothelial Cells (HUVECs) senescence. Autophagy activity was measured through immunofluorescence and immunohistochemistry staining of light chain 3 (LC3) expression. Inhibition of ER activity was established using shRNA gene silencing and ER antagonist. Compared with ER-β knockdown, we found that knockdown of ER-α resulted in a significant increase in the extent of HUVEC senescence and senescence-associated secretory phenotype (SASP) secretion. ER-α-specific shRNA was found to reduce 17β-E2-induced autophagy, promote HUVEC senescence, disrupt the morphology of HUVECs, and increase the expression of Rb dephosphorylation and SASP. These in vitro findings were found consistent with the in vivo results. In conclusion, our data suggest that 17β-E2 activates the activity of ER-α and then increases the formation of autophagosomes (LC3 high expression) and decreases the fusion of lysosomes with autophagic vesicles (P62 low expression), which in turn serves to decrease the secretion of SASP caused by H2O2 and consequently inhibit H2O2-induced senescence in HUVEC cells.
... Estrogen influences the basal forebrain of the rat and regulates the cholinergic neurons that project into the cerebral cortex and hippocampus involved in cognitive enhancement [29]. E2 also induces acetylcholinesterase and choline acetyltransferase (ChAT) activity, suggesting a general trophic effect on cholinergic neurons [29][30][31][32]. E2 administration prevents neurodegeneration in the brain due to declining estrogen levels during menopause [33] and blocks the actions of neurotoxic agents or inhibits their generation [34][35][36]. ...
The localization and expression of amylin protein in the rodent brain and mouse neuroblastoma Neuro-2a (N2a) are less widely known. Thus, this study investigated the expression distribution of amylin in the rat brain and N2a treated with steroid hormones. Amylin protein was identified in the olfactory bulb, cerebral cortex, dentate gyrus, thalamus, hypothalamus, ventral tegmental area (VTA), cerebellum, and brain stem in the rat brain. Additionally, the amylin protein was localized with the mature neurons of the cerebral cortex and dopaminergic neurons of the VTA. Progesterone (P4) and dexamethasone (Dex) significantly decreased, and 17β-estradiol (E2) increased the amylin protein level in the cerebral cortex. The P4 receptor antagonist RU486 significantly influenced the effects of P4 and Dex, and the E2 receptor antagonist ICI 182,780 slightly changed E2′s effect. Amylin protein expression was significantly reduced in the VTA by P4 and Dex, and its expression was changed only following P4 plus RU486 treatment. It was confirmed for the first time that amylin protein is strongly expressed in the cytoplasm in N2a cells using immunofluorescent staining. P4 increased the levels of amylin, and RU486 treatment decreased them. Dex significantly increased the levels of amylin protein. RU486 treatment reversed the effects of Dex. Therefore, amylin protein is expressed in the cerebral cortex neurons and dopaminergic neurons of the VTA of the immature rat brain. P4 and Dex influence the expression of amylin protein in the rat brain and N2a cells.
... Results on inhibition and selective attention performance varied, being either impaired or improved in LaF and improved or unimproved with high E2 levels, depending on the task [133,137,138]. Two studies on spatial memory suggested that high E2 levels were related to improved performance [139,140]. ...
Female athletes have garnered considerable attention in the last few years as more and more women participate in sports events. However, despite the well-known repercussions of female sex hormones, few studies have investigated the specificities of elite female athletes. In this review, we present the current but still limited data on how normal menstrual phases, altered menstrual phases, and hormonal contraception affect both physical and cognitive performances in these elite athletes. To examine the implicated mechanisms, as well as the potential performances and health risks in this population, we then take a broader multidisciplinary approach and report on the causal/reciprocal relationships between hormonal status and mental and physical health in young (18–40 years) healthy females, both trained and untrained. We thus cover the research on both physiological and psychological variables, as well as on the Athlete Biological Passport used for anti-doping purposes. We consider the fairly frequent discrepancies and summarize the current knowledge in this new field of interest. Last, we conclude with some practical guidelines for eliciting improvements in physical and cognitive performance while minimizing the health risks for female athletes.
... Epidemiological analyses have revealed that women receiving HRT in their perimenopausal period are at a lower risk of AD (Henderson and Brinton, 2010), while those untreated are more likely to suffer from AD (Rocca et al., 2008;Rocca et al., 2010). A growing number of studies suggests that ovarian hormones, including E2 and progesterone, play a neuroprotective role (Pike et al., 2009;Engler-Chiurazzi et al., 2016). However, large clinical trials have indicated that HRT causes serious side effects on the breast and uterus (Beral and Million Women Study Collaborators, 2003). ...
Background: Impairment of memory and cognition is one of the major symptoms in women with postmenopausal disorders due to estrogen deficiency, which accounts for the much higher prevalence of Alzheimer’s disease in females. Biochanin A (BCA), a natural phytoestrogen, has been reported to protect neurons against ischemic brain injury. However, the neuroprotective effects of BCA in the postmenopausal-like model of ovariectomized (OVX) rats remain to be investigated.
Methods: All the rats except for the sham group underwent the resection of bilateral ovaries. Seven days after the OVX surgery, rats were randomly divided into six groups: sham, OVX, OVX + BCA (5 mg/kg), OVX + BCA (20 mg/kg), OVX + BCA (60 mg/kg), and OVX + estradiol (E2; 0.35 mg/kg), which were administrated daily by gavage for 12 weeks. Learning and memory were examined using the Morris water-maze test before the end of the experiment. Morphological changes of the rat hippocampus were observed by HE staining and electron microscopy. Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) in the hippocampus were measured. The effect of BCA on cell viability was measured in the presence of hydrogen peroxide (H 2 O 2 ) using CCK8. Flow cytometry was used to measure neuronal apoptosis and reactive oxygen species (ROS) induced by H 2 O 2 . Expression of Bcl-2, Bax, and Caspase-3 was determined by Western blotting using hippocampal tissues and primary cultures of hippocampal neurons.
Results: Chronic treatment with BCA mimicked the ability of E2 to reverse the deficit of learning and memory in the Morris water-maze test in OVX rats. BCA normalized OVX-induced morphological changes as revealed by HE staining and electron microscopy. In addition, BCA significantly decreased the levels of MDA, the biomarker of oxidative damage, and increased the activity of the intracellular antioxidant enzymes SOD and GSH-Px in OVX rats. Further, in primary cultures of hippocampal neurons, BCA reversed H 2 O 2 -induced decreases in cell viability and accumulation of ROS. Finally, BCA reversed OVX- or H 2 O 2 -induced increases in Bax and Caspase-3 and decreases in Bcl-2 in the hippocampus and primary cultures of hippocampal neurons.
Conclusion: These results suggest that BCA improves memory through its neuroprotective properties in the brain under the circumstance of estrogen deficiency and can be used for treatment of memory loss in postmenopausal women.
... Their notable actions on the hippocampus and prefrontal cortex, in particular, have also been reported. It has been reported, in rodents, that exogenous estradiol administration reverses the decreases in the dendritic spine density of neurons in the hippocampus and prefrontal cortex caused by an ovariectomy, as well as improving the memory [91][92][93]. The detailed actions are yet to be thoroughly elucidated; however, their receptor distributions are wide across brains, and complex interactions with multiple neurotransmitter systems, as described in previous sections, conveniently place them as a key player in cognitive functioning. ...
Increasing evidence suggests estrogen and estrogen signaling pathway disturbances across psychiatric disorders. Estrogens are not only crucial in sexual maturation and reproduction but are also highly involved in a wide range of brain functions, such as cognition, memory, neurodevelopment, and neuroplasticity. To add more, the recent findings of its neuroprotective and anti-inflammatory effects have grown interested in investigating its potential therapeutic use to psychiatric disorders. In this review, we analyze the emerging literature on estrogen receptors and psychiatric disorders in cellular, preclinical, and clinical studies. Specifically, we discuss the contribution of estrogen receptor and estrogen signaling to cognition and neuroprotection via mediating multiple neural systems, such as dopaminergic, serotonergic, and glutamatergic systems. Then, we assess their disruptions and their potential implications for pathophysiologies in psychiatric disorders. Further, in this review, current treatment strategies involving estrogen and estrogen signaling are evaluated to suggest a future direction in identifying novel treatment strategies in psychiatric disorders.
... Previously, we demonstrated that PMI-006 decreased FJC+ staining and reduced microglial activation in rats after TBI [29] and the neuroprotective properties of E2 are established (for review, see Engler-Chiurazzi et al., 2016 [30]). MicroRNA microarray profiling of naïve, shaminjured, TBI or TBI plus drug treatments (JM6, E2 or PMI) revealed that all three neuroprotective drugs restored TBI induced miRNA profiles to sham-injury patterns (Fig 2A). ...
Patients with traumatic brain injury (TBI) are frequently diagnosed with depression. Together, these two leading causes of death and disability significantly contribute to the global burden of healthcare costs. However, there are no drug treatments for TBI and antidepressants are considered off-label for depression in patients with TBI. In molecular profiling studies of rat hippocampus after experimental TBI, we found that TBI altered the expression of a subset of small, non-coding, microRNAs (miRNAs). One known neuroprotective compound (17β-estradiol, E2), and two experimental neuroprotective compounds (JM6 and PMI-006), reversed the effects of TBI on miRNAs. Subsequent in silico analyses revealed that the injury-altered miRNAs were predicted to regulate genes involved in depression. Thus, we hypothesized that drug-induced miRNA profiles can be used to identify compounds with antidepressant properties. To confirm this hypothesis, we examined miRNA expression in hippocampi of injured rats treated with one of three known antidepressants (imipramine, fluoxetine and sertraline). Bioinformatic analyses revealed that TBI, potentially via its effects on multiple regulatory miRNAs, dysregulated transcriptional networks involved in neuroplasticity, neurogenesis, and circadian rhythms- networks known to adversely affect mood, cognition and memory. As did E2, JM6, and PMI-006, all three antidepressants reversed the effects of TBI on multiple injury-altered miRNAs. Furthermore, JM6 reduced TBI-induced inflammation in the hippocampus and depression-like behavior in the forced swim test; these are both properties of classic antidepressant drugs. Our results support the hypothesis that miRNA expression signatures can identify neuroprotective and antidepressant properties of novel compounds and that there is substantial overlap between neuroprotection and antidepressant properties.
... Several mechanisms have been implicated to mediate E2 neuroprotection in the brain. For instance, our group and others have shown that E2 neuroprotection can involve genomic signaling, nongenomic signaling, antioxidative functions, and regulation of mitochondrial bioenergetics, as well as anti-inflammatory actions [19][20][21][22][23][24]. The classical estrogen receptors, ER-α and ER-β, as well as the new putative G-protein coupled estrogen receptor 1 (GPER1), have been implicated to mediate E2 neuroprotection in the brain [6,14,18,[25][26][27][28][29][30][31][32][33][34]. ...
17 β -Estradiol (E2) is a well-known neuroprotective hormone, but its role in regulation of neuroinflammation is less understood. Recently, our lab demonstrated that E2 could regulate the NLRP3 (NOD-like receptor protein 3) inflammasome pathway in the hippocampus following global cerebral ischemia (GCI). Here, we examined the ability of E2 to regulate activation and polarization of microglia phenotype in the hippocampus after global cerebral ischemia (GCI). Our in vivo study in young adult ovariectomized rats showed that exogenous low-dose E2 profoundly suppressed microglia activation and quantitatively shifted microglia from their “activated,” amoeboid morphology to a “resting,” ramified morphology after GCI. Further studies using M1 “proinflammatory” and M2 “anti-inflammatory” phenotype markers showed that E2 robustly suppressed the “proinflammatory” M1 phenotype, while enhancing the “anti-inflammatory” M2 microglia phenotype in the hippocampus after GCI. These effects of E2 may be mediated directly upon microglia, as E2 suppressed the M1 while enhancing the M2 microglia phenotype in LPS- (lipopolysaccharide-) activated BV2 microglia cells in vitro . E2 also correspondingly suppressed proinflammatory while enhancing anti-inflammatory cytokine gene expression in the LPS-treated BV2 microglia cells. Finally, E2 treatment abolished the LPS-induced neurotoxic effects of BV2 microglia cells upon hippocampal HT-22 neurons. Collectively, our study findings suggest a novel E2-mediated neuroprotective effect via regulation of microglia activation and promotion of the M2 “anti-inflammatory” phenotype in the brain.
... In addition, numerous reports have confirmed a substantial neuroprotective role for estradiol in models of neurodegenerative diseases, but the focus of this review is on traumatic brain injury and stroke models (Pérez-Alvarez & Wandosell 2013, Engler-Chiurazzi et al. 2016, Melcangi et al. 2016, Perez-Alvarez & Wandosell 2016. ...
Among sex steroid hormones, progesterone and estradiol have a wide diversity of physiological activities that target the nervous system. Not only are they carried by the blood stream, but also they are locally synthesized in the brain and for this reason, estradiol and progesterone are considered 'neurosteroids'. The physiological actions of both hormones range from brain development and neurotransmission to aging, illustrating the importance of a deep understanding of their mechanisms of action. In this review, we summarize key roles that estradiol and progesterone play in the brain. As numerous reports have confirmed a substantial neuroprotective role for estradiol in models of neurodegenerative disease, we focus this review on traumatic brain injury and stroke models. We describe updated data from receptor and signaling events triggered by both hormones, with an emphasis on the mechanisms that have been reported as 'rapid' or 'cytoplasmic actions'. Data showing the therapeutic effects of the hormones, used alone or in combination, are also summarized, with a focus on rodent models of middle cerebral artery occlusion (MCAO). Finally, we draw attention to evidence that neuroprotection by both hormones might be due to a combination of 'cytoplasmic' and 'nuclear' signaling.
... Epidemiological analyses have revealed that women who received hormone therapy in their perimenopausal period are at a lower risk for AD [8], while those untreated are more likely to suffer from AD [9,10]. A growing number of reports suggest that ovarian hormones [11,12], including E2 and progesterone, play a neuroprotective role. However, the effect of sex hormone treatment for AD still remains to be explored [13]. ...
Epidemiologic studies have demonstrated that women account for two-thirds of Alzheimer's disease (AD) cases, for which the decline in circulating gonadal hormone is considered to be one of the major risk factors. In addition, ovarian hormone deficiency may affect β-amyloid (Aβ) deposition, which has a close relationship with autophagic flux. In this study, we investigated the impact of short-term or long-term ovarian hormone deprivation on two mouse models, the non-transgenic (wild-type) and the APP/PS1 double-transgenic AD (2×TgAD) model. Autophagy-related proteins (Beclin1, LC3, and p62) and lysosome-related proteins were detected to evaluate Aβ deposition and autophagy. Our results showed that in the group with short-term depletion of ovarian hormones by ovariectomy (ovx), Beclin1, Cathepsin B (Cath-B), and LAMP1 levels were significantly decreased, while the levels of LC3-II and p62 were increased. In the long-term group, however, there was a sharp decline in Beclin1, LC3-II, Cath-B, and LAMP1 expression but not in p62 expression which is increased. It is worthwhile to note that the occurrence of neuritic plaque-induced ovarian hormone loss increased both the Aβ level and neuritic plaque deposition in 2×TgAD mice. Therefore, autophagy may play an important role in the pathogenesis of female AD, which is also expected to help post-menopausal patients with AD.
... Furthermore, subchronic treatment with E2 in ovariectomized (OVX) rats increases ChAT mRNA expression in basal forebrain neurons (Gibbs, 2000) and modulates the expression of neurotrophin receptors, such as TrkA, in this same brain region (Milne et al., 2015). E2 also induces cyclic changes in spine density and dendritic morphology, thus playing an important role as a protective agent against several types of injury (Engler-Chiurazzi et al., 2016). Some of these changes were blocked by the lesion of basal forebrain cholinergic neurons, which co-express E2 receptors along with neurotrophin receptors (Bora et al., 2005). ...
Treatment with 17-β estradiol and progesterone improves the performance of ovariectomized rats in an autoshaping learning task, representing cognitive improvement. To test whether this is attributable to genomic mechanisms, the antiestrogen ICI 182 780 or antiprogesterone RU486 was injected into ovariectomized animals primed previously with estrogen or progesterone, respectively. Compared with the vehicle control, each hormone administered alone produced an elevated expression of choline acetyltransferase and TrkA, along with an improvement in performance on the behavioral test. E2+ICI reverted the increase in these two proteins. However, RU alone elicited higher ChAT expression. With this exception, there was a clear linear regression between the number of conditioned responses and the level of ChAT and TrkA in the basal forebrain. The results suggest that TrkA may be more important than ChAT for regulating autoshaping learning tasks, and that genomic mechanisms in the basal forebrain could possibly underlie hormonal improvement of cognition.
... The neuroprotective potential of estrogens was recently extensively reviewed by Engler-Chiurazzi and co-authors (2016) [71]. The estrogen 17β-estradiol (E2) showed protective effects on RGCs in different experimental models of glaucoma [72][73][74], including the ischemia-reperfusion injury model [75]. ...
Background:
Glaucoma is a progressive optic neuropathy characterized by retinal ganglion cell death and alterations of visual field. Elevated intraocular pressure (IOP) is considered the main risk factor of glaucoma, even though other factors cannot be ruled out, such as epigenetic mechanisms.
Objective:
An overview of the ultimate promising experimental drugs to manage glaucoma has been provided.
Results:
In particular, we have focused on purinergic ligands, KATP channel activators, gases (nitric oxide, carbon monoxide and hydrogen sulfide), non-glucocorticoid steroidal compounds, neurotrophic factors, PI3K/Akt activators, citicoline, histone deacetylase inhibitors, cannabinoids, dopamine and serotonin receptors ligands, small interference RNA, and Rho kinase inhibitors.
Conclusions:
The review has been also endowed of a brief chapter on last reports about potential neuroprotective benefits of anti-glaucoma drugs already present in the market.
... For instance, adult female rats which received 10 μg day À1 17β-oestradiol for 3 weeks demonstrated enhanced working and reference memory (Uzum et al., 2016). Another study suggests oestrogens could attenuate disease-associated cognitive deficits and reduce Alzheimer's disease risk (Engler-Chiurazzi et al., 2016). Outside the nervous system, phytoestrogens have been found to have a boneprotective effect in osteoporosis in ovariectomized rats (Fu et al., 2014). ...
Correct perinatal oestrogen levels are critical for sexual differentiation. For example, perinatal exposure to oestrogen causes masculinization and defeminization of the brain in female rats and also induces delayed effects after maturation characterized by early onset of abnormal oestrus cycling. However, the mechanisms underlying the above effects of oestrogen remain to be fully determined. 17α-ethinyloestradiol (EE), a common synthetic oestrogen widely used in oral contraceptives, binds specifically to oestrogen receptors. In this study, we demonstrated the effects of a single neonatal injection of high- or low-dose EE on reproductive behaviours. Female rats within 24 h after birth were subcutaneously injected with sesame oil, EE (0.02, 2 mg kg(-1) ) and 17β-oestradiol (E2 ) (20 mg kg(-1) ). Between 11 and 15 weeks of age, sexual behaviour was tested twice in a paced mating situation. Latency to enter, lordosis and soliciting behaviour were recorded. Both high-dose EE- and E2 -treated females showed a significantly lower lordosis quotient, decreased soliciting behaviours, increased rejection and fighting numbers. Accessibility to males was also delayed by neonatal E2 exposure, although it was shortened by high-dose EE exposure. In contrast, low-dose EE-treated females did not exhibit impaired sexual behaviour. These results suggest that single neonatal exposure to a high dose of EE or E2 disturbs the normal development of the female brain, resulting in impaired sexual behaviours in a female-paced mating situation. Besides, the differences noted between high-dose EE- and E2 -treated females might be caused by different affinities of the oestrogen receptors, metabolic rates or mechanisms of action. Copyright © 2017 John Wiley & Sons, Ltd.
... In contrast to young women, older women (over 65 years old) have an increased incidence of stroke and higher morbidity and mortality after stroke compared to age-matched men (Appelros et al., 2009). It has been proposed that the higher rates of stroke, as well as the poorer recovery from stroke in senior women, is due to a decrease in circulating gonadal hormones (Engler-Chiurazzi et al., 2016). However, the risk of stroke does not increase in women until several decades past menopause. ...
... Endocrine therapies, first used more than 100 years ago, are one of the most effective treatments for estrogen receptor positive breast cancer [227]. Hormonal supplementation in peri-and postmenopausal women is a promising preventive or treatment option for neurodegenerative conditions such as AD [228]. However, due to side effects, including heightened risk of breast cancer, coronary heart disease and stroke, associated with hormone replacement therapy (HRT), it remains a source of great health concern [229,230]. ...
The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer's disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer's disease.
... Considering the data from basic research and epidemiological trials, one could hypothesize that HT has a beneficial effect on cognition [3,[6][7][8][9][10]14] but a large, longterm, double-blind randomized clinical trial known as the Women's Health Initiative Memory Study (WHIMS) showed that in cognitively unimpaired women, HT can increase the risk of cognitive decline [11,12,15,16]. Recently, a new clinical trial has emerged, the Kronos Early Estrogen Prevention Study (KEEPS), whose substudy the Cognitive and Affective Study (KEEPS-Cog) reported that there is no beneficial effect of HT on cognition [13]. ...
Hormone therapy (HT) is prescribed during or after menopausal transition to replace the decline in estrogen and progesterone levels. While some studies indicate that estrogen and progesterone depletion in postmenopausal women might carry a significant risk for developing sporadic Alzheimer’s disease (sAD), which may be reduced by HT, recent clinical trials oppose this beneficial effect. This review points to possible reasons for these mixed data by considering the issues of both preclinical and clinical trials, in particular, the representativeness of animal models, timing of HT initiation, type of HT (different types of estrogen compounds, estrogen monotherapy vs. estrogen-progesterone combined therapy), mode of drug delivery (subcutaneous, transdermal, oral, or intramuscular), and hormone dosage used, as well as the heterogeneity of the postmenopausal population in clinical trials (particularly considering their sAD stage, anti-AD therapy, and hysterectomy status). Careful planning of future preclinical and clinical HT interventional studies might help to elucidate the effect of HT on cognitive status in postmenopausal women with sAD, which will eventually contribute to more effective sAD prevention and treatment.
... Considering the data from basic research and epidemiological trials, one could hypothesize that HT has a beneficial effect on cognition [3,[6][7][8][9][10]14] but a large, longterm, double-blind randomized clinical trial known as the Women's Health Initiative Memory Study (WHIMS) showed that in cognitively unimpaired women, HT can increase the risk of cognitive decline [11,12,15,16]. Recently, a new clinical trial has emerged, the Kronos Early Estrogen Prevention Study (KEEPS), whose substudy the Cognitive and Affective Study (KEEPS-Cog) reported that there is no beneficial effect of HT on cognition [13]. ...
Alterations in glucose metabolism occur in the brain in the early stage of Alzheimer’s disease (AD), and menopausal women have more severe metabolic dysfunction and are more prone to dementia than men. Although estrogen deficiency-induced changes in glucose metabolism have been previously studied in animal models, their molecular mechanisms in AD remain elusive. To investigate this issue, double transgenic (APP/PS1) female mice were subjected to bilateral ovariectomy at 3 months of age and were sacrificed 1 week, 1 month and 3 months after surgery to simulate early, middle and late postmenopause, respectively. Our analysis demonstrated that estrogen deficiency exacerbates learning and memory deficits in this mouse model of postmenopause. Estrogen deficiency impairs the function of mitochondria in glucose metabolism. It is possible that the occurrence of AD is associated with the aberrant mitochondrial ERβ-mediated IGF-1/IGF-1R/GSK-3β signaling pathway. In this study, we established a potential mechanism for the increased risk of AD in postmenopausal women and proposed a therapeutic target for AD due to postmenopause.
Since neuroprotection in stroke should be revisited in the era of recanalization, the current study analyzes the potential neuroprotective effect of the selective estrogen receptor modulator, bazedoxifene acetate (BZA), in an animal model of diabetic ischemic stroke that mimics thrombectomy combined with adjuvant administration of a putative neuroprotectant. Four weeks after induction of diabetes (40 mg/kg streptozotocin, i.p.), male Wistar rats were subjected to transient middle cerebral artery occlusion (tMCAO, intraluminal thread technique, 60 min) and distributed in three groups: vehicle‐, BZA‐ (3 mg/kg/day, i.p.) and 17β‐estradiol‐ (E2, 100 μg/kg/day, i.p.) treated animals. At 24 post‐ischemia‐reperfusion, brain damage (neurofunctional score, infarct size and apoptosis), expression of estrogen receptors (ERα, ERβ and GPER), and activity of the MAPK/ERK1/2 and PI3K/Akt pathways were analyzed. At 24 h after the ischemic insult, both BZA‐ and E2‐treated animals showed lower brain damage in terms of improved neurofunctional condition, decreased infarct size, and decreased apoptotic cell death. Ischemia‐reperfusion induced a significant decrease in ERα and ERβ expression without affecting that of GPER; BZA and E2 reversed such a decrease. The ischemic insult upregulated activity of both MAPK/ERK1/2 and PI3K/Akt pathways; BZA and E2 attenuated the increased activity of the ERK1/2 pathway, without affecting that of the Akt pathway. The current study lends further support to the consideration of BZA as an effective and safer alternative overcoming the drawbacks of E2 in improving diabetic ischemic stroke outcome after successful reperfusion.
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Estrogens are the primary female sex hormones and play important roles in both reproductive and non-reproductive organs. They are synthesized in non-reproductive tissues such as liver, heart, muscle, bone and brain, and tissue-specific estrogen synthesis is consistent with a diversity of estrogen actions. In this chapter, we discuss tissue and cell-specific estrogen synthesis and estrogen receptor signaling during ageing in reproductive system and non reproductive tissue especially in the brain and age related alteration and diseases. Estrogens act through two types of nuclear receptors, viz ERα, ERβ and cell-membrane receptors viz GPR30 and ER-X. These types of ERs are expressed in the reproductive organs and brain. For example, estrogens secreted from ovary play key roles in the reproductive system, such as puberty onset, fertility and the estrous cycle. Recent studies have shown that brain estrogens protect against insult-induced neuronal damages. Ageing is an inevitable process where brain undergoes structural, physiological and functional changes. During ageing, level of estrogen, ERs and binding of transcriptions factors to ER promoter decline with age. Moreover, the expression of coregulators and their interaction with ERs show variation during brain ageing. Further, the findings like identification of consensus CK2, PKC and N-myristoylation sites among ERβ interacting brain nuclear and mitochondrial proteins and deviation from LxxxLL motifs have opened new research avenues in the context of estrogen signaling. Such studies might be useful in exploring the therapeutic potential of estrogens in reproductive and neurological diseases. This warrants extensive research in the area of estrogen and ageing.
Since publication of the results of the Women Health Initiative Memory Study demonstrating that hormone therapy initiated late after menopause increases the risk of dementia in women, attempts have been made to identify a “critical window of intervention”. In the meantime, basic research carried out in the last 10–15 years has reinforced the concept of a strong impact of estrogen in neuroprotection, moving also into novel directions that include characterization of estrogen's effect on non-neuronal cells, mitochondrial function, miRNA production and novel targets for their action in the central nervous system (CNS). All these findings, together with a list of recent animal models of Alzheimer's Disease that appear feasible for the study of estrogen's CNS effect are here summarized and accompanied by the most recent data from clinical trials in which hormone therapy was initiated early after menopause.
As the knowledge on the estrogenic system in the brain grows, the possibilities to modulate it in order to afford further neuroprotection in brain damaging disorders so do it. We have previously demonstrated the ability of the selective estrogen receptor modulator, bazedoxifene (BZA), to reduce experimental ischemic brain damage. The present study has been designed to gain insight into the molecular mechanisms involved in such a neuroprotective action by investigating: 1) stroke-induced apoptotic cell death; 2) expression of estrogen receptors (ER) ERα, ERβ and the G-protein coupled estrogen receptor (GPER); and 3) modulation of MAPK/ERK1/2 and PI3K/Akt signaling pathways. For comparison, a parallel study was done with 17β-estradiol (E2)-treated animals. Male Wistar rats subject to transient right middle cerebral artery occlusion (tMCAO, intraluminal thread technique, 60 min), were distributed in vehicle-, BZA- (20.7 ± 2.1 ng/mL in plasma) and E2- (45.6 ± 7.8 pg/mL in plasma) treated groups. At 24 h from the onset of tMCAO, RT-PCR, Western blot and histochemical analysis were performed on brain tissue samples. Ischemia-reperfusion per se increased apoptosis as assessed by both caspase-3 activity and TUNEL-positive cell counts, which were reversed by both BZA and E2. ERα and ERβ expression, but not that of GPER, was reduced by the ischemic insult. BZA and E2 had different effects: while BZA increased both ERα and ERβ expression, E2 increased ERα expression but did not change that of ERβ. Both MAPK/ERK1/2 and PI3K/Akt pathways were stimulated under ischemic conditions. While BZA strongly reduced the increased p-ERK1/2 levels, E2 did not. Neither BZA nor E2 modified ischemia-induced increase in p-Akt levels. These results show that modulation of ERα and ERβ expression, as well as of the ERK1/2 signaling pathway accounts, at least in part, for the inhibitory effect of BZA on the stroke-induced apoptotic cell death. This lends mechanistic support to the consideration of BZA as a potential neuroprotective drug in acute ischemic stroke treatment.
Menopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women.
KEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 μg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes. On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was -5.36 × 10-2 (95% CI, -8.27 × 10-2 to -2.44 × 10-2; ES = 0.49, p < 0.001) and for the anxiety subscale was -3.01 × 10-2 (95% CI, -5.09 × 10-2 to -9.34 × 10-3; ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importantly, the KEEPS-Cog results cannot be extrapolated to treatment longer than 4 y.
The KEEPS-Cog findings suggest that for recently postmenopausal women, MHT did not alter cognition as hypothesized. However, beneficial mood effects with small to medium ESs were noted with 4 y of o-CEE, but not with 4 y of t-E2. The generalizability of these findings is limited to recently postmenopausal women with low cardiovascular risk profiles.
ClinicalTrials.gov NCT00154180 and NCT00623311.
The hypothalamo-pituitary-adrenal (HPA) axis represents a complex neuroendocrine feedback loop controlling the secretion of adrenal glucocorticoid hormones. Central to its function is the paraventricular nucleus of the hypothalamus (PVN) where neurons expressing corticotropin releasing factor reside. These HPA motor neurons are a primary site of integration leading to graded endocrine responses to physical and psychological stressors. An important regulatory factor that must be considered, prior to generating an appropriate response is the animal's reproductive status. Thus, PVN neurons express androgen and estrogen receptors and receive input from sites that also express these receptors. Consequently, changes in reproduction and gonadal steroid levels modulate the stress response and this underlies sex differences in HPA axis function. This review examines the make up of the HPA axis and hypothalamo-pituitary-gonadal (HPG) axis and the interactions between the two that should be considered when exploring normal and pathological responses to environmental stressors.
Importance:
Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention.
Objective:
To report a comprehensive, integrated overview of findings from the 2 Women's Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up.
Design, setting, and participants:
A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers.
Interventions:
Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010.
Main outcomes and measures:
Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death.
Results:
During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials.
Conclusions and relevance:
Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.
Trial registration:
clinicaltrials.gov Identifier: NCT00000611.
The mechanism by which the estrogen receptor and other steroid hormone receptors regulate gene expression in eukaryotic cells is not well understood. In this study, a complementary DNA clone containing the entire translated portion of the messenger RNA for the estrogen receptor from MCF-7 human breast cancer cells was sequenced and then expressed in Chinese hamster ovary (CHO-K1) cells to give a functional protein. An open reading frame of 1785 nucleotides in the complementary DNA corresponded to a polypeptide of 595 amino acids and a molecular weight of 66,200, which is in good agreement with published molecular weight values of 65,000 to 70,000 for the estrogen receptor. Homogenates of transformed Chinese hamster ovary cells containing a protein that bound [3H]estradiol and sedimented as a 4S complex in salt-containing sucrose gradients and as an 8 to 9S complex in the absence of salt. Interaction of this receptor-[3H]estradiol complex with a monoclonal antibody that is specific for primate ER confirms the identity of the expressed complementary DNA as human estrogen receptor. Amino acid sequence comparisons revealed significant regional homology among the human estrogen receptor, the human glucocorticoid receptor, and the putative v-erbA oncogene product. This suggests that steroid receptor genes and the avian erythroblastosis viral oncogene are derived from a common primordial gene. The homologous region, which is rich in cysteine, lysine, and arginine, may represent the DNA-binding domain of these proteins.
Alzheimer's disease is one of the most common causes of mental deterioration in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witnessed a considerable research effort directed towards discovering the cause of Alzheimer's disease with the ultimate hope of developing safe and effective pharmacological treatments. This article examines the existing scientific applicability of the original cholinergic hypothesis of Alzheimer's disease by describing the biochemical and histopathological changes of neurotransmitter markers that occur in the brains of patients with Alzheimer's disease both at postmortem and neurosurgical cerebral biopsy and the behavioural consequences of cholinomimetic drugs and cholinergic lesions. Such studies have resulted in the discovery of an association between a decline in learning and memory, and a deficit in excitatory amino acid (EAA) neurotransmission, together with important roles for the cholinergic system in attentional processing and as a modulator of EAA neurotransmission. Accordingly, although there is presently no "cure" for Alzheimer's disease, a large number of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed efficacy in delaying the deterioration of symptoms of Alzheimer's disease, a valuable treatment target considering the progressive nature of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer's disease, first tacrine and more recently, donepezil and rivastigmine, all of which are cholinesterase inhibitors.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose etiology is presently unknown. Probably the most consistent and widespread deficit seen in this syndrome is that of the basal forebrain cholinergic system. We have previously demonstrated that estradiol (E2) modulates the function of these neurons and plays a role in their maintenance by preventing the ovariectomy-induced decrease in choline acetyltransferase activity. It has been postulated that the lack of neurotrophic support may contribute at least in part to degeneration of cholinergic neurons in AD. As such, it is hypothesized that E2 may affect cholinergic function by modulating the levels of certain neurotrophic factors. We have shown that 3 months after ovariectomy (OVX) there was a significant reduction in NGF messenger RNA (mRNA) levels. In the present study, we extended the hypothesis that E2 may serve a neurotrophomodulatory role by assessing the effect of OVX and E2 replacement on brain-derived nerve factor (BDNF) mRN...
There is ample empirical evidence to support the notion that the biological impacts of estrogen extend beyond the gonads to other bodily systems, including the brain and behavior. Converging preclinical findings have indicated a neuroprotective role for estrogen in a variety of experimental models of cognitive function and brain insult. However, the surprising null or even detrimental findings of several large clinical trials evaluating the ability of estrogen-containing hormone treatments to protect against age-related brain changes and insults, including cognitive aging, stroke, and traumatic brain injury, led to hesitation by both clinicians and patients in the use of exogenous estrogenic treatments for nervous system outcomes. That estrogen-containing therapies are used by tens of millions of women for a variety of health-related applications across the lifespan has made identifying conditions under which benefits with estrogen treatment will be realized an important public health issue. Here we provide a summary of the biological actions of estrogen and estrogen-containing formulations. We have devoted special attention to highlighting the notion that estrogen appears to be a conditional neuroprotectant whose efficacy is modulated by several interacting factors. By developing criteria standards for desired beneficial peripheral and neuroprotective outcomes among unique patient populations, we can optimize estrogen treatments for attenuating the consequences of, and perhaps even preventing, cognitive aging and brain injury.
Objectives:
We hypothesized that oral estrogen replacement therapy would be less common among elderly women meeting criteria for Alzheimer's disease (AD) than among nondemented elderly women. For women with AD, we hypothesized that estrogen users would perform better on a cognitive task than would nonusers.
Design:
A case-control study of estrogen replacement therapy, in which hierarchical procedures were used to control for potentially confounding effects of age and education. When cognitive performances were compared between estrogen users and nonusers with AD, the duration of dementia symptoms was an additional control variable.
Setting:
Alzheimer's Disease Research Center at the University of Southern California, Los Angeles.
Subjects:
Subjects were a volunteer sample of consecutively enrolled elderly women, recruited primarily from the community, who met clinical criteria for probable AD (n=143) or met criteria for nondemented control status (n=92). Seventy case patients who have subsequently died met histopathologic criteria for AD; one other demented woman who did not meet the autopsy criteria for AD was excluded from all analyses.
Main Outcome Measures:
Current use of estrogen replacement at the time of enrollment as reported by control subjects or by the primary caregivers of AD case patients. Among cases, performances on a brief cognitive screening instrument were compared between estrogen users (n=10) and nonusers (n=128) for whom this information was available.
Results:
Alzheimer's disease case patients were significantly less likely than control subjects to use estrogen replacement (7% vs 18%), but groups did not differ with regard to the total number of prescription medications or to the most frequently prescribed class of drug (thyroid medication). Demented case patients using estrogen did not differ significantly from those not using estrogen in terms of age, education, or symptom duration, but their mean performance on a cognitive screening instrument was significantly better (Mini-Mental State examination scores of 14.9 vs 6.5).
Conclusions:
Findings are consistent with contentions that postmenopausal estrogen replacement therapy may be associated with a decreased risk of AD and that estrogen replacement may improve cognitive performance of women with this illness.
Subarachnoid hemorrhage (SAH) is a unique disorder commonly occurring when an aneurysm ruptures, leading to bleeding and clot formation, with a higher incidence in females. To evaluate the influence of 17- estradiol (E2) in the outcome of subarachnoid hemorrhage, SAH was induced by endovascular puncture of the intracranial segment of internal carotid artery in 15 intact females (INT), 19 ovariectomized females (OVX), and 13 ovariectomized female rats with E2 replacement (OVX + E2). Cerebral blood flow was recorded before and after SAH. All animals were decapitated immediately after death or 24 hours after SAH for clot area analysis. Brains were sliced and stained with 2,3,5-triphenyltetrazolium chloride (TTC) for secondary ischemic lesion analysis. The cortical cerebral blood flow (CBF), which was measured by a laser–Doppler flowmeter, decreased to 29.6% 17.7%, 22.8% 8.3%, and 43.5% 22.9% on the ipsilateral side (P = 0.01), and decreased to 63.4% 14.1%, 57.4% 11.0%, and 66.6% 17.9% on the contralateral side (P = 0.26) in INT, OVX, and OVX + E2, respectively. The subcortical CBF, which were measured by the H2 clearance method, were 7.77 12.03, 7.80 8.65, and 20.58 8.96 mL 100 g-1 min-1 on the ipsilateral side (P < 0.01), and 21.53 2.94, 25.13 3.01, and 25.30 3.23 mL 100 g-1 min-1 on the contralateral side in INT, OVX, and OVX + E2, respectively. The mortality was 53.3%, 68.4%, and 15.4% in INT, OVX, and OVX + E2, respectively (P = 0.01), whereas no significant difference in clot area was noted among the groups. The secondary ischemic lesion volume was 9.3% 8.4%, 24.3% 16.3%, and 7.0% 6.4% in INT, OVX, and OVX + E2, respectively (P < 0.01). This study demonstrated that E2 can reduce the mortality and secondary ischemic damage in a SAH model without affecting the clot volume.Keywords: Estrogens, Subarachnoid hemorrhage, Ischemia, Neuroprotection
Estrogens are neuroprotectants against a variety of insults, both in vitro and in vivo. Many of these insults involve an oxidative stress component and estrogens are known antioxidants. We (Green et al. [1997b] J Steroid Biochem Mol Biol 63:229–235) and others (Behl et al. [1997] Mol Pharmacol 51:535–541; Moosmann and Behl [1999] Proc Natl Acad Sci USA 96:8867–8872) have determined that the phenolic nature of the A-ring of the estradiol molecule is essential for neuroprotection. We performed structure-activity relationship studies using a library of estratriene compounds in well-established in vitro models for neuroprotection. We tested over 70 compounds in HT-22 (murine hippocampal) cells for their ability to inhibit cell toxicity against glutamate and iodoacetic acid, at two doses for each insult, and determined EC50 values to ascertain potency comparisons with 17β-estradiol (E2). We verified that a phenolic A ring was essential for neuroprotection in these models. We also observed that hydrophobicity and planarity affects the ability of estratrienes to protect cells from oxidative stress. This neuroprotection correlated with their ability to inhibit iron-induced lipid peroxidation in vitro. In contrast, the ability of these estratrienes to bind estrogen receptors was negatively correlated with their ability to protect cells from oxidative stress or inhibit lipid peroxidation. Drug Dev. Res. 66:78–92, 2006. © 2006 Wiley-Liss, Inc.
Principal findings on dementia from the Women's Health Initiative Memory Study (WHIMS) showed that conjugated equine estrogens plus medroxyprogesterone acetate (CEE/MPA) increase dementia risk in women aged 65 years and above, but not risk of mild cognitive impairment. The dementia finding was unexpected, given consistent observational evidence that associates use of estrogen-containing hormone therapy with reduced risk of Alzheimer's disease. It remains controversial whether hormone use by younger postmenopausal women near the time of menopause reduces dementia risk or whether WHIMS findings should be generalized to younger women. Given the challenges of conducting a primary prevention trial to address that question, it is helpful to consider the impact of hormone therapy on cognitive test performance, particularly verbal memory, for its own sake and as a proxy for dementia risk. The WHI Study of Cognitive Aging (WHISCA) showed that CEE/MPA worsened verbal memory, whereas CEE alone had no influence on cognition. These findings have been replicated in several randomized, clinical trials. The apparent negative effect of CEE/MPA on verbal memory does not appear to be age-dependent. Additional investigations are needed to understand the impact of other hormonally active compounds on dementia and cognitive outcomes.
Gonadectomized male and female rats were treated with equimolar doses of estradiol benzoate (EB) and testosterone propionate (TP) daily for periods of 3 days to 1 week and activities of monoamine oxidase (MAO) and choline acetyltransferase (ChAc) were measured in the cortex, hippocampus, basomedial hypothalamus, corticomedial amygdala and medial preoptic areas. After hormone treatment, changes in enzyme activities were found in those brain regions where gonadal hormones are known to affect sexual behavior and/or gonadotropin release and which contain putative hormone receptor sites. More specifically, EB administration to females resulted in decreased activity of MAO in the corticomedial amygdala and basomedial hypothalamus and an elevation of ChAc activity in the medial preoptic area and corticomedial amygdala while TP administration did not alter enzyme levels in any brain region. In contrast, EB administration to castrated males was without significant effect on enzyme activities while TP administration resulted in increased activity of MAO and ChAc in the medial-preoptic area. The estrogen antagonist, MER-25, given concomitantly with EB, effectively blocked EB-dependent changes in both enzymes in ovariectomized female rats. EB treatment to hypophysectomized females led to similar enzymatic changes as in ovariectomized females in all areas except the basomedial hypothalamus. Estradiol added directly to the enzyme incubation medium did not result in altered enzyme activities. Results obtained are discussed in relation to sexual differentiation of the brain, metabolism of gonadal hormones, and possible mechanism of gonadal hormone regulation of enzyme activities.
In the 50 years since the initial reports of a cognate estrogen receptor (ER), much has been learned about the diverse effects and mechanisms of estrogens, such as 17β-estradiol (E2). This expert narrative review briefly summarizes perspectives and/or recent work of the authors, who have been addressing different aspects of estrogen action, but take a common approach of using alternative considerations to gain insight into mechanisms with clinical relevance, and inform future studies, regarding estrogen action. Their “Top Ten” favorite alternatives that are discussed herein are as follows. 1 — E2 has actions by binding to a receptor that do not require its enzymatic conversion. 2 — Using a different strategy for antibody binding could make the estrogen receptor (ER) more discernible. 3 — Blocking ERs, rather than E2 production, may be a useful strategy for breast cancer therapy. 4 — Secretion of α-fetoprotein (AFP), rather than only levels of E2 and/or progesterone, may influence breast cancer risk. 5 — A peptide derived from the active site of AFP can produce the same benefits of the entire endogenous protein in endocrine cancers. 6 — Differential distribution of ER subtypes in the body and brain may underlie specific effects of estrogens. 7 — ERβ may be sufficient for the trophic effects of estrogen in the brain, and ERα may be the primary target of trophic effects in the body. 8 — ERβ may play a role in the trophic effects of androgens, and may also be relevant in the periphery. 9 — Downstream of E2's effects at ERβ, there may be consequences for biosynthesis of progestogens and/or androgens. 10 — Changes in histones and/or other factors, which may be downstream of ERβ, potentially underlie the divergent effects of E2 in the brain and peripheral tissues.
The 1959 publication of the paper by Phoenix et al. was a major turning point in the study of sexual differentiation of the brain. That study showed that sex differences in behavior, and by extension in the brain, were permanently sexually differentiated by testosterone, a testicular secretion, during an early critical period of development. The study placed the brain together in a class with other major sexually dimorphic tissues (external genitalia and genital tracts), and proposed an integrated hormonal theory of sexual differentiation for all of these non-gonadal tissues. Since 1959, the organizational-activational theory has been amended but survives as a central concept that explains many sex differences in phenotype, in diverse tissues and at all levels of analysis from the molecular to the behavioral. In the last two decades, however, sex differences have been found that are not explained by such gonadal hormonal effects, but rather because of the primary action of genes encoded on the sex chromosomes. To integrate the classic organizational and activational effects with the more recently discovered sex chromosome effects, we propose a unified theory of sexual differentiation that applies to all mammalian tissues.
This review describes recent advances made in the understanding of the regulation of acetylcholine synthesis in brain with regard to the availability of its two precursors, choline and acetylCoA. Choline availability appears to be regulated by the high affinity choline transport system. Investigations of the localization and inhibition of this system are reviewed. Procedures for measuring high affinity choline transport and their shortcomings are described. The kinetics and effects of previous in vivo and in vitro treatments on high affinity choline transport are reviewed. Kinetic and direct coupling of the transport and acetylation of choline are discussed. Recent investigations of the source of acetylCoA used for the synthesis of acetylcholine are reviewed. Three sources of acetylCoA have recently received support: citrate conversion catalyzed by citrate lyase, direct release of acetylCoA from mitochondria following its synthesis from pyruvate catalyzed by pyruvate dehydrogenase, and production of acetylCoA by cytoplasmic pyruvate dehydrogenase. Investigations indicating that acetylCoA availability may limit acetylcholine synthesis are reviewed. A model for the regulation of acetylcholine synthesis which incorporates most of the reviewed material is presented.
The distribution of estrogen receptor mRNA expression was studied in the developing rat cerebral cortex by in situ hybridization histochemistry. We used a specific, nonisotopically (digoxigenin) labeled, synthetic oligodeoxyribonucleotide complementary to a 48 base sequence in the region of the estrogen-binding domain of rat uterine estrogen receptor cDNA. During development, estrogen receptor mRNA was observed in all forebrain regions previously reported to bind estrogen, as determined by steroid autoradiography or nuclear binding assay. In the developing cerebral cortex, estrogen receptor mRNA was extensively expressed in the ventricular zone, primitive plexiform layer, and immature cortical plate at least as early as embryonic day 16. During the first 3 postnatal weeks, cortical mRNA expression was increasingly restricted to the upper third of the cerebral cortex and to the neurons of the cortical subplate (layer VIb/VII) and decreased to low levels by postnatal day 28. In the cerebral cortex, the spatial distribution of estrogen receptor mRNA expression overlapped that reported for the encoded protein. The extensive distribution of estrogen receptor mRNA throughout the late prenatal and early postnatal cerebral cortex points to an important role for estrogen in the differentiation and maturation of the cerebral cortex.
Administration of estradiol to gonadectomized female, but not male rats, is associated with increased activity of choline acetyltransferase in the medial aspect of the horizontal diagonal band nucleus, the frontal cortex, and CA1 of the dorsal hippocampus. Four other basal forebrain cholinergic nuclei did not show changes in choline acetyltransferase activity after estradiol. These data have implications for possible benefits of estradiol administration to patients with senile dementia of the Alzheimer's type.
Microdissection techniques were utilized to measure the activity of choline acetyltransferase (ChAT) (enzyme responsible for synthesis of acetylcholine) in individual basal forebrain nuclei of aged (24 month) and young (4 month) male and female rats. Small but consistent decreases in the activity of ChAT in aged rats were found, and the location of the changes was dependent on the sex of the rat. Aged female rats showed approximately 30% lower ChAT and 40% lower acetylcholinesterase (AChE) activity in the ventral globus pallidus (vGP). Aged males did not show decreased ChAT in the vGP but activity in the medial aspect of the horizontal diagonal band nucleus was 50% lower than in the young males. ChAT activity in four other closely aligned basal forebrain nuclei was not different between the young and aged rats. Analysis of cell number, density and area in the vGP by AChE histochemistry showed no significant differences between aged and young females. In addition, age and sex-dependent changes were measured in pituitary glucose-6-phosphate dehydrogenase activity. The relationship of the changes to age-dependent decrements in memory, the possible influence of gonadal hormones on aging, and the mechanisms responsible for age-related declines in ChAT activity are discussed.
Previous studies have suggested that estrogen may have an effect on cognitive and emotional function in women. Studies in rodents and non-human primates have demonstrated the presence of estrogen receptors in brain, and that estrogen can affect behavior in animals. Estrogen administration to ovariectomized rats increases choline acetyltransferase activity in certain regions of brain. Choline acetyltransferase activity is known to be significantly decreased in senile dementia-Alzheimer's type (SDAT). Based on these observations, we treated seven women with SDAT with low dosages of estradiol over a six week period. A battery of assessments was performed throughout the study period. Significant improvements in three women were noted on measures of attention, orientation, mood and social interaction. These estrogen-responsive women were characterized by dementia associated with an affective disorder, older age at onset, and evidence of osteoporosis. Side effects of estradiol therapy included withdrawal bleeding in one woman and transient breast tenderness in another. Estradiol therapy thus may benefit some postmenopausal women with SDAT. The occurrence of osteoporosis in the estrogen-responsive group suggests that SDAT in some women may be associated with or related to a systemic estrogen deficiency state. However, considering the potential for serious side effects as a result of estrogen therapy, the current risk to benefit ratio precludes the routine clinical use of estrogen for dementia until careful clinical research trials have been performed.
The nucleus basalis magnocellularis (NBM) is the name given to a group of cholinesterase-reactive neurons in the ventromedial corner of the globus pallidus of the rat. This cell group appears to be the major extrinsic source of cortical acetylcholine and is believed to be homologous to the nucleus basalis of Meynert in primates. The excitotoxin ibotenic acid (2.4 micrograms/0.4 microliter) was infused bilaterally into the ventromedial globus pallidus. These lesions depleted frontal cortical choline acetyltransferase (CAT) by a third. Neurotoxic lesions of the dorsolateral globus pallidus did not affect cortical CAT activity. Neither lesion affected the rats' performance on a battery of psychomotor tasks or on tests of shock sensitivity. Rats with NBM lesions were mildly impaired in the acquisition of a one-way active avoidance response, but did not differ from the other groups on extinction of the task. The NBM lesioned rats exhibited a severe deficit in the retention of a passive avoidance response. This effect was visible both 24 hours and one hour after training. Experimental controls suggested that the poor performance of the NBM lesioned rats involves a deficit in learning and/or memory of the training trial. Lesions of the dorsolateral globus pallidus also produced an impairment of passive avoidance retention, but this impairment was not as severe as that following NBM lesions. These results are discussed as they relate to the behavioral role of cholinergic innervation of the cortex, and the development of animal models for disorders involving cortical cholinergic deficiencies, including senile dementia of the Alzheimer's type.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose etiology is presently unknown. Probably the most consistent and widespread deficit seen in this syndrome is that of the basal forebrain cholinergic system. We have previously demonstrated that estradiol (E2) modulates the function of these neurons and plays a role in their maintenance by preventing the ovariectomy-induced decrease in choline acetyltransferase activity. It has been postulated that the lack of neurotrophic support may contribute at least in part to degeneration of cholinergic neurons in AD. As such, it is hypothesized that E2 may affect cholinergic function by modulating the levels of certain neurotrophic factors. We have shown that 3 months after ovariectomy (OVX) there was a significant reduction in NGF messenger RNA (mRNA) levels. In the present study, we extended the hypothesis that E2 may serve a neurotrophomodulatory role by assessing the effect of OVX and E2 replacement on brain-derived nerve factor (BDNF) mRNA levels using in situ hybridization. BDNF mRNA levels were quantified in three groups of animals: ovary-intact animals, 28-week ovariectomized (OVX) animals, and E2-replaced OVX animals. Twenty-eight weeks after OVX, there were significant reductions in two of the three cerebral cortical regions analyzed [frontal (35%) and temporal (39%) cortexes], but E2 replacement was without effect. Twenty-eight weeks after OVX, there were also reductions in BDNF mRNA in all subregions of the hippocampus except CA1 (CA2 by 38%, CA3 by 44%, CA4 by 39%, and dentate gyrus by 37%), whereas E2 replacement was effective in elevating BDNF mRNA levels in the CA3, CA4, and dentate gyrus subregions. Collectively, the data demonstrate that E2 deprivation leads to a reduction in BDNF mRNA. Further, at the time point studied, E2 replacement is more effective in maintaining BDNF mRNA in the hippocampus than in the cortex, suggesting a regional difference in the ovarian steroid requirement for expression of BDNF.
The rapid activation of stress-responsive neuroendocrine systems is a basic reaction of animals to perturbations in their environment. One well-established response is that of the hypothalamo-pituitary-adrenal (HPA) axis. In rats, corticosterone is the major adrenal steroid secreted and is released in direct response to adrenocorticotropin (ACTH) secreted from the anterior pituitary gland. ACTH in turn is regulated by the hypothalamic factor, corticotropin-releasing hormone. A sex difference exists in the response of the HPA axis to stress, with females reacting more robustly than males. It has been demonstrated that in both sexes, products of the HPA axis inhibit reproductive function. Conversely, the sex differences in HPA function are in part due to differences in the circulating gonadal steroid hormone milieu. It appears that testosterone can act to inhibit HPA function, whereas estrogen can enhance HPA function. One mechanism by which androgens and estrogens modulate stress responses is through the binding to their cognate receptors in the central nervous system. The distribution and regulation of androgen and estrogen receptors within the CNS suggest possible sites and mechanisms by which gonadal steroid hormones can influence stress responses. In the case of androgens, data suggest that the control of the hypothalamic paraventricular nucleus is mediated trans-synaptically. For estrogen, modulation of the HPA axis may be due to changes in glucocorticoid receptor-mediated negative feedback mechanisms. The results of a variety of studies suggest that gonadal steroid hormones, particularly testosterone, modulate HPA activity in an attempt to prevent the deleterious effects of HPA activation on reproductive function.
The present study provides evidence that 17-beta-estradiol (E2) exerts cytoprotective effects on both glial and neuronal cell lines. In C6 rat glioma cells, the addition of E2 to serum free media enhances live cell number by 40% at 24 h and 75% at 96 h when compared to serum free media conditions. E2 treatment of C6 cells in serum free medium did not increase thymidine uptake at any sampling time, indicating that the observed effect of E2 on C6 cell number was not due to a mitogenic effect of the steroid hormone. The addition of E2 to SK-N-SH cells in serum free media maintained both total and live cell number at a level comparable to the fetal bovine serum (FBS) treated cells at both 24 and 48 h. At 96 h after treatment with E2, total and live cell numbers were diminished relative to the 48-h sample and the 96-h FBS group, but were still more than twice the number observed in serum free media. Associated with the reduced effects of E2 at 96 h was an increase in the ratio of dead to total cells, although it remained about 50% less than the serum free group. Through 48 h, E2 exposure did not increase thymidine uptake in SK-N-SH cells, indicating that the effect of E2 on SK-N-SH cells was cytoprotective rather than mitogenic. Collectively, these data support a cytoprotective action of E2 on neuronal or glial cell types in vitro.
We hypothesized that estradiol (E2) serves as a neurotrophomodulatory substance for basal forebrain cholinergic neurons thought to be involved in learning and memory. Learning/memory was assessed using the two-way active avoidance paradigm and the Morris water task. Female Sprague-Dawley rats were either ovariectomized (OVX) or OVX for 3 weeks, followed by s.c. implantation of a Silastic pellet containing 17-beta E2 (E2 pellet), resulting in a replacement of E2 to physiological levels. Ovary-intact (INTACT) animals served as our positive control. Active avoidance behavior and choline acetyltransferase (ChAT) activity in the frontal cortex and hippocampus were assessed at 5 and 28 weeks postovariectomy while performance on the Morris water task and high-affinity choline uptake (HACU) were measured only at the 5-week time point. At the 5-week time point, E2 replacement caused a significant elevation in the level of active avoidance performance relative to OVX animals. At the 28-week time point, OVX animals demonstrated a significantly lower number of avoidances relative to controls (61%) whereas E2-pellet animals not only demonstrated superior performance relative to OVX animals but also showed an accelerated rate of learning. Morris water task performance, on the other hand, was not significantly affected by estrogenic milieu despite a trend towards better performance in the E2-pellet group. Neurochemical analyses revealed that 5 weeks of ovariectomy was sufficient to reduce HACU in both the frontal cortex and hippocampus by 24 and 34%, respectively, while E2 replacement was successful in elevating HACU relative to OVX animals in both regions.(ABSTRACT TRUNCATED AT 250 WORDS)
We hypothesized that oral estrogen replacement therapy would be less common among elderly women meeting criteria for Alzheimer's disease (AD) than among nondemented elderly women. For women with AD, we hypothesized that estrogen users would perform better on a cognitive task than would nonusers.
A case-control study of estrogen replacement therapy, in which hierarchical procedures were used to control for potentially confounding effects of age and education. When cognitive performances were compared between estrogen users and nonusers with AD, the duration of dementia symptoms was an additional control variable.
Alzheimer's Disease Research Center at the University of Southern California, Los Angeles.
Subjects were a volunteer sample of consecutively enrolled elderly women, recruited primarily from the community, who met clinical criteria for probable AD (n = 143) or met criteria for nondemented control status (n = 92). Seventy case patients who have subsequently died met histopathologic criteria for AD; one other demented woman who did not meet the autopsy criteria for AD was excluded from all analyses.
Current use of estrogen replacement at the time of enrollment as reported by control subjects or by the primary caregivers of AD case patients. Among cases, performances on a brief cognitive screening instrument were compared between estrogen users (n = 10) and nonusers (n = 128) for whom this information was available.
Alzheimer's disease case patients were significantly less likely than control subjects to use estrogen replacement (7% vs 18%), but groups did not differ with regard to the total number of prescription medications or to the most frequently prescribed class of drug (thyroid medication). Demented case patients using estrogen did not differ significantly from those not using estrogen in terms of age, education, or symptom duration, but their mean performance on a cognitive screening instrument was significantly better (Mini-Mental State examination scores of 14.9 vs 6.5).
Findings are consistent with contentions that postmenopausal estrogen replacement therapy may be associated with a decreased risk of AD and that estrogen replacement may improve cognitive performance of women with this illness.
Estrogen-replacement therapy has been associated with a reduced incidence of Alzheimer's disease (AD) and improved cognition in several small open clinical trials. We assessed the possibility that estrogens may reduce toxicity of beta-amyloid (A beta) by testing the effects of beta-estradiol on the toxicity of the neurotoxic fragment of beta-amyloid (A beta 25-35) in SK-N-SH neuroblastoma cells. A beta 25-35 caused a dose-dependent death in SK-N-SH cells with a LD50 of 28.9 muM. In cultures simultaneously exposed to 20 muM A beta and 17 beta-estradiol (2 nM). A beta-induced toxicity was reduced by 83 and 51% in two separate studies. Further studies show that 0.2 nM 17 beta-estradiol was as effective as the 2 nM concentration. 17 alpha-Estradiol (2 nM) conferred neuroprotection equivalent to that of 17 beta-estradiol. These data support the hypothesis that estrogens reduce beta-amyloid toxicity and this may help explain the beneficial effects of estrogens in AD.
Oxidative stress-induced neuronal cell death has been implicated in different neurological disorders and neurodegenerative diseases; one such ailment is Alzheimer's disease. Using the Alzheimer's disease-associated amyloid beta protein, glutamate, hydrogen peroxide, and buthionine sulfoximine, we investigated the neuroprotective potential of estrogen against oxidative stress-induced cell death. We show that 17-beta-estradiol, its nonestrogenic stereoisomer, 17-alpha-estradiol, and some estradiol derivatives can prevent intracellular peroxide accumulation and, ultimately, the degeneration of primary neurons, clonal hippocampal cells, and cells in organotypic hippocampal slices. The neuroprotective antioxidant activity of estrogens is dependent on the presence of the hydroxyl group in the C3 position on the A ring of the steroid molecule but is independent of an activation of estrogen receptors.
Recent evidence supports a role for estrogens in both normal neural development and neuronal maintenance throughout life. Women spend 25-33% of their life in an estrogen-deprived state and retrospective studies have shown an inverse correlation between dose and duration of estrogen replacement therapy (ERT) and incidence of Alzheimer's disease (AD), suggesting a role for estrogen in the prevention and/or treatment of neurodegenerative diseases. To explore these observations further, an animal model was developed using ovariectomy (OVX) and ovariectomy with estradiol replacement (E2) in female Sprague-Dawley rats to mimic postmenopausal changes. Using an active-avoidance paradigm and a spatial memory task, the effects of estrogen deprivation were tested on memory-related behaviors. OVX caused a decline in avoidance behavior, and estrogen replacement normalized the response. In the Morris water task of spatial memory, OVX animals showed normal spatial learning but were deficient in spatial memory, an effect that was prevented by estrogen treatment. Together these data indicate that OVX in rats results in an estrogen-reversible impairment of learning/memory behavior. Because a plethora of information has been generated that links decline in memory-related behavior to dysfunction of cholinergic neurons, the effects of estrogens on cholinergic neurons were tested. We demonstrated that OVX causes a decrease in high affinity choline uptake and choline acetyltransferase activity in the hippocampus and frontal cortex; ERT reverses this effect. Further, we showed that estrogens promote the expression of mRNA for brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), 2 neurotrophic substances that have been shown to ameliorate the effects of age and injury on cholinergic neurons. Tissue culture models were used to evaluate whether estrogen treatment increases the survival of neurons when exposed to a variety of insults. 17-beta-Estradiol (beta-E2) protects cells from the neurotoxic effects of serum deprivation and hypoglycemia in human neuroblastoma cell lines. We have also observed that 17-alpha-estradiol (alpha-E2), a weak estrogen, shows neuroprotective efficacy in the SK-N-SH cell line at concentrations equivalent to beta-E2. Finally, we have observed that tamoxifen, a classic estrogen antagonist, blocks only one-third of the neuroprotective effects of either alpha-E2 or beta-E2. Collectively, these results indicate that estrogen is behaviorally active in tests of learning/ memory; activates basal forebrain cholinergic neurons and neurotrophin expression; and is neuroprotective for human neuronal cultures. We conclude that estrogen may be a useful therapy for AD and other neurodegenerative diseases.
The present study was undertaken to determine if estrogens protect female rats from the neurodegenerative effects of middle cerebral artery (MCA) occlusion. The rats were ovariectomized and 7 or 8 days later various estrogen preparations were administered before or after MCA occlusion. Pretreatment with 17beta-estradiol (17beta-E2) or a brain-targeted 17beta-E2 chemical delivery system (CDS) decreased mortality from 65% in ovariectomized rats to 22% in 17beta-E2-treated and 16% in 17beta-E2 CDS-treated rats. This marked reduction in mortality was accompanied by a reduction in the ischemic area of the brain from 25.6+/-5.7% in the ovariectomized rats to 9.8+/-4% and 9.1+/-4.2% in the 17beta-E2-implanted and the 17beta-E2 CDS-treated rats, respectively. Similarly, pretreatment with the presumed inactive estrogen, 17alpha-estradiol, reduced mortality from 36 to 0% and reduced the ischemic area by 55 to 81%. When administered 40 or 90 minutes after MCA occlusion, 17beta-E2 CDS reduced the area of ischemia by 45 to 90% or 31%, respectively. In summary, the present study provides the first evidence that estrogens exert neuroprotective effects in an animal model of ischemia and suggests that estrogens may be a useful therapy to protect neurons against the neurodegenerative effects of stroke.
Estrogens are reported to reduce the incidence of Alzheimer's disease and 17beta-estradiol (betaE2), the potent, naturally occurring estrogen, exerts neuroprotective effects in a variety of in vivo and in vitro model systems. The present study elucidates the structural requirements of steroids and related compounds for neuroprotectivity at low nM doses. All estrogens tested with an intact phenolic A ring protected SK-N-SH neuroblastoma cells from the toxic effects of serum-deprivation. All 3-O-methyl ether cogeners tested were inactive indicating the importance of a phenolic A ring. The diphenolic estrogen mimic diethylstilbesterol (DES) was neuroprotective and retention of a single phenolic function was sufficient to retain neuroprotective activity. The di-O-methyl ether of DES was inactive. The following steroids which lack a phenolic A ring were also inactive: testosterone; dihydrotestosterone; progesterone; corticosterone; prednisolone; 6 alpha-methylprednisolone; aldosterone; and cholesterol. Finally, phenol, lipophilic phenols, and tetrahydronapthol were inactive. These results suggest that a phenolic A ring and at least three rings of the steroid nucleus are necessary for the neuroprotective activity of estrogens.
The present studies were undertaken to investigate the effects of gender and estrogen treatment on focal cerebral ischemia in male and female rats. Focal ischemia was created by inserting a 3-0 surgical suture through the left cervical internal carotid artery to obstruct the blood flow into the middle cerebral artery (MCA). The MCA was reperfused by removing the suture in 40 min. All rats were sacrificed for measurement of infarct area after 24 h. In the first study, mortalities from MAC occlusion were 12.5% (2/16) each for intact male rats and intact female rats, and 23.5% (4/17) for ovariectomized (OVX) female rats. The coronal infarct area (mean+/-S. E.M.) was 9.5+/-1.0% for intact female rats, 16.6+/-1.6% for intact male rats (p=0.0001 vs. intact female rats), and 16.0+/-1.4% for OVX female rats (p=0.0002 vs. intact female rats). In a second experiment, OVX-female rats were administrated either 17beta-estradiol (E2) or its vehicle, hydroxypropyl-beta-cyclodextrin (HPCD), at 40 min after the onset of MCA occlusion. Mortalities were 40% (4/10) for vehicle treated OVX rats and 0% for E2 treated OVX rats. The coronal infarct area (mean+/-S.E.M.) was 19.3+/-1.8% for vehicle treated rats vs. 8.0+/-1. 2% for E2 treated rats (p<0.01). Serum estrogen levels for vehicle treated OVX rats were 14.5+/-1.2% pg/ml vs. 142.7+/-23.6 pg/ml for E2 treated OVX rats (p<0.01). These results strongly suggest that the level of circulating estrogens play an important role in protecting brain tissues against ischemia induced by MCA occlusion.
This review starts with an historical background of the pharmacological development of tacrine almost fifty years ago (1949). Tacrine is the first drug to be tested, clinically, on a large scale and to be registered (1993) for treatment of Alzheimer's disease. For the first time, clinical results of four second generation cholinesterase inhibitors (ChEI) (donepezil, ENA 713, eptastigmine and metrifonate) are reviewed and compared with other ChEI such as tacrine, physostigmine and galanthamine. Data based on more than 6000 patients show that second generation drugs are well tolerated and show evidence of clinical efficacy. Differences are mainly due to frequency of side effects, number of drop outs and percentage of improved patients. These results also demonstrate the presence of clinical efficacy for all ChEI tested so far. Clinical mechanism of action, levels of efficacy and differences among various ChEI are discussed. Future potential indications are suggested. The present data indicate that optimization of effects prolongation and maintenance of clinical gains will depend on further knowledge of the compounds pharmacodynamic properties.
Choline acetyltransferase (ChAT), the enzyme responsible for the biosynthesis of acetylcholine, is presently the most specific indicator for monitoring the functional state of cholinergic neurones in the central and peripheral nervous systems. ChAT is a single-strand globular protein. The enzyme is synthesized in the perikaryon of cholinergic neurones and transported to the nerve terminals probably by both slow and rapid axoplasmic flows. ChAT exists in at least two forms in cholinergic nerve terminals: (i) soluble; and (ii) non-ionically membrane-bound forms. Multiple mRNA species of ChAT (R-, N-and M-types) are transcribed from different promoter regions and produced by different splicing in the mouse, rat, and human. All transcripts encode the same ChAT protein in rodents, while in human M-type mRNA has the capability to generate both large and small forms of ChAT proteins and R-and N-types ChAT mRNA generate a small form, which corresponds to the rodent ChAT. The genomic structure of ChAT is unique compared with other enzymes for neurotransmitters. The first intron of the ChAT gene encompasses the open reading frame encoding another protein, vesicular acetylcholine transporter (VAChT), which is responsible for the transportation of acetylcholine from the cytoplasm into the synaptic vesicles. The expressions of ChAT and VAChT appear to be coordinately regulated by multiple regulatory elements in cholinergic neurones. Immunohistochemical and in situ hybridization studies have revealed the localization of cholinergic neurones in the central nervous system: the medial septal nucleus, the nucleus of the diagonal band of Broca, the basal nucleus of Meynert, the caudate nucleus, the putamen, the nucleus accumbens, the pedunculopontine tegmental nucleus, the laterodorsal tegmental nucleus, the medial habenular nucleus, the parabigeminal nucleus, some cranial nerve nuclei, and the anterior horn of the spinal cord. Focally distributed cholinergic neurones project fibers to many areas in the central nervous system and construct a complicated cholinergic network, playing an important role in neuropsychic activities, such as learning, memory, arousal, sleep and movement. Central cholinergic neurones are involved in several neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis, in which disturbance of the central cholinergic system does not appear to be closely related to the etiology, but rather to the development of clinical symptoms. In addition, abnormalities of ChAT in the brain have been recently demonstrated in schizophrenia and sudden infant death syndrome.
17beta-Estradiol (E2) has been reported to exert neuroprotective effects when administered before an ischemic insult. This study was designed to determine whether E2 treatment after ischemia exerts the same effects and, if so, how long this therapeutic window remains open, and whether the effects are related to changes in cerebral blood flow (CBF).
Female Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO). In protocol 1, E2 was administered (100 microg/kg IV followed immediately by subcutaneous implantation of crystalline E2 in a silicone elastomer tube) to ovariectomized females (OVX+E2) at 0.5 (n=8), 1 (n=6), 2 (n=7), 3 (n=6), or 4 (n=9) hours after MCAO. Intact (INT; n=6) and ovariectomized females (OVX; n=12) were subjected to MCAO and received vehicle instead of E2. Two days after MCAO the animals were killed, and ischemic lesion volume was determined by 2,3,5-triphenyltetrazolium chloride staining. In protocol 2, CBF was monitored before and at 1, 24, and 48 hours in a group of animals receiving E2 or vehicle 0.5 hour after ischemia induction (INT, n=6; OVX, n=8; OVX+E2, n=6).
Lesion volume was 20.9+/-2.2% and 21.8+/-1.2% in the INT and OVX groups, respectively. E2 was found to decrease lesion volume significantly when administered within 3 hours after MCAO. The lesion volumes were 6.3+/-0.5%, 10.3+/-2.1%, 11.8+/-1.8%, 13.5+/-1.6%, and 17.9+/-2.8% when E2 was administered at 0.5, 1, 2, 3, or 4 hours after MCAO, respectively. CBF decreased to 43.1+/-2.2% and 25.4+/-1.0% in the INT and OVX animals, respectively, at 5 minutes after MCAO. In comparison to OVX rats, CBF was not different at 1 hour after E2 administration but was increased significantly in the OVX+E2 group 1 and 2 days after E2 administration.
E2 exerts neuroprotective effects when administered after ischemia, with a therapeutic window in a permanent focal cerebral ischemia model of approximately 3 hours. This effect of estradiol was associated with no immediate change in blood flow but with a delayed increase in CBF.
Interest in the effects of hormone therapy on health outcomes among
postmenopausal women has perhaps never been greater. As recently reported,1 the Women's Health Initiative (WHI) randomized clinical
trial of postmenopausal hormone therapy terminated the combined estrogen-progestin
arm (but not the estrogen-only arm) early after an average follow-up of 5.2
years (planned duration, 8.5 years).2 Women
who received estrogen plus progestin experienced a small but significant increase
in the primary outcome, coronary heart disease; a nonsignificant trend toward
an increase in the primary adverse outcome, invasive breast cancer; and a
significant increase in a global index (which included the 2 primary outcomes
plus stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip
fracture, and death due to other causes) summarizing risk and benefit. However,
the decision to stop this portion of the trial did not take into account several
other important outcomes that may affect a woman's choice of whether to take
hormone therapy, including potential effects on cognition. Two ancillary studies
to the WHI randomized trial focus on risk of dementia and cognitive decline,
but these outcomes are not considered in the WHI risk-benefit profile.
We have synthesized a library of estrogen analogues, including enantiomers of estradiol and A-ring substituted estrogens. These compounds have reduced or no binding to either estrogen receptor-alpha or estrogen receptor-beta, exhibit enhanced neuroprotective activity in in vitro models, and are potent in protecting brain tissue from cerebral ischemia/reperfusion injury. These potent, nonfeminizing estrogen analogues are prime candidates for use in stroke neuroprotection.
Estrogens are potent neuroprotectants both in vitro and in vivo. In the present study, we compared the potency and efficacy of a non-feminizing estrogen, 2-(1-adamantyl)-4-methylestrone (ZYC-26), with its parent estrogen, estrone, and an expected non-neuroprotective 3-O-methyl analog of (17beta)-2-(1-adamantyl)estradiol (ZYC-23). These estratriene derivatives were tested for their ability to protect in an in vitro lipid peroxidation model, to neuroprotect against oxidative stress in cell culture models, to bind the estrogen receptors (ERalpha and ERbeta), to elicit uterotrophic effects, and to affect brain damage from transient middle cerebral artery occlusion. We observed that in contrast to estrone, neither ZYC-26 nor ZYC-23 bound to either estrogen receptors (ER) and both failed to elicit a uterotrophic response. In vitro, the active estrogen analogue ZYC-26 was more potent that estrogen in its ability to inhibit lipid peroxidation and to protect HT-22 cells from either glutamate or iodoacetic acid (IAA) toxicity. Further, ZYC-26 was as active in preventing brain damage from transient middle cerebral artery occlusion (MCAO) as was estrone. Collectively, these studies suggest that the antioxidant activity, rather than ER binding of non-feminizing estrogens such as ZYC-26, mediates their potent neuroprotective activity. Further, in view of the now known toxicities of chronic feminizing estrogen use in older women, non-feminizing estrogens may be a useful alternative for estrogen-induced brain protection.
This review summarizes current knowledge of the genetic and hormonal control of sexual differentiation of the reproductive system, brain and brain function. While the chromosomal regulation of sexual differentiation has been understood for over 60 years, the genes involved and their actions on the reproductive system and brain are still under investigation. In 1990, the predicted testicular determining factor was shown to be the SRY gene. However, this discovery has not been followed up by elucidation of the actions of SRY, which may either stimulate a cascade of downstream genes, or inhibit a suppressor gene. The number of other genes known to be involved in sexual differentiation is increasing and the way in which they may interact is discussed. The hormonal control of sexual differentiation is well-established in rodents, in which prenatal androgens masculinize the reproductive tract and perinatal oestradiol (derived from testosterone) masculinizes the brain. In humans, genetic mutations have revealed that it is probably prenatal testosterone that masculinizes both the reproductive system and the brain. Sexual differentiation of brain structures and the way in which steroids induce this differentiation, is an active research area. The multiplicity of steroid actions, which may be specific to individual cell types, demonstrates how a single hormonal regulator, e.g. oestradiol, can exert different and even opposite actions at different sites. This complexity is enhanced by the involvement of neurotransmitters as mediators of steroid hormone actions. In view of current environmental concerns, a brief summary of the effects of endocrine disruptors on sexual differentiation is presented.
The cholinergic hypothesis of Alzheimer׳s disease: a review of progress
- Francis
Estrogen replacement therapy in older women. Comparisons between Alzheimer׳s disease cases and nondemented control subjects
- Henderson