Roles of estrogen receptors alpha and beta in sexually dimorphic neuroprotection against glutamate toxicity

Bryant, Damani N.; Dorsa, Daniel M.

doi:10.1016/j.neuroscience.2010.08.019

Cited by 47 publications

(26 citation statements)

References 47 publications

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“…ER␤ has been characterized as predominantly antiproliferative and pro-apoptotic in cancer models, in contrast to the proliferative and antiapoptotic role of ER␣. However, in the brain, both receptors demonstrate protection against various neurological insults such as ischemia and glutamate toxicity (26,27). E2 can induce anti-apoptotic factors such as Bcl-2 (28 -31), and overexpression of Bcl-2 can induce nuclear localization of factors such as ANXA1 (32).…”

Section: Discussionmentioning

confidence: 99%

Age-dependent Effects of 17β-estradiol on the Dynamics of Estrogen Receptor β (ERβ) Protein–Protein Interactions in the Ventral Hippocampus

Mott

Pinceti

Rao

et al. 2014

Molecular & Cellular Proteomics

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Recent clinical evidence suggests that the neuroprotective and beneficial effects of hormone therapy may be limited by factors related to age and reproductive status. The patient's age and length of time without circulating ovarian hormones are likely to be key factors in the specific neurological outcomes of hormone therapy. However, the mechanisms underlying age-related changes in hormone efficacy have not been determined. We hypothesized that there are intrinsic changes in estrogen receptor ␤ (ER␤) function that determine its ability to mediate the actions of 17␤-estradiol (E2) in brain regions such as the ventral hippocampus. In this study, we identified and quantified a subset of ER␤ protein interactions in the ventral hippocampus that were significantly altered by E2 replacement in young and aged animals, using two-dimensional differential gel electrophoresis coupled with liquid chromatography-electrospray ionization-tandem mass spectrometry. This study demonstrates quantitative changes in ER␤ protein-protein interactions with E2 replacement that are dependent upon age in the ventral hippocampus and how these changes could alter processes such as transcriptional regulation. Thus, our data provide evidence that changes in ER␤ protein interactions are a potential mechanism for age-related changes in E2 responsiveness in the brain after menopause. Molecular & Cellular Proteomics 13: 10.1074/mcp.M113.031559, 760-779, 2014.The neuroprotective and beneficial effects of estrogens in the brain have been reported for decades, yet recent evidence from clinical trials suggests that the benefits of estrogens in postmenopausal women might not outweigh the risks (1-3). Specifically, the risk of cardiovascular disease and invasive breast cancer was significantly increased in postmenopausal women given hormone therapy as part of the largest clinical trial performed to date (Women's Health Initiative). These results sharply contradicted substantial evidence from numerous studies in animal models, prompting a reevaluation of the data from the Women's Health Initiative studies. Later it was determined that factors contributing to the observed detrimental effects of hormone therapy in the Women's Health Initiative study included advanced age, the types of synthetic estrogens and progestins used in the study, and, perhaps most important, the number of years postmenopause prior to the initiation of hormone therapy (4). However, more than 10 years after the conclusion of these studies there is little to no mechanistic explanation for how aging contributes to a change in estrogen signaling.One possibility is that there are age-related changes in the way the brain responds to estrogens. We hypothesized that there are intrinsic changes in the function of estrogen receptors in the brain with advanced age, and estrogen receptor ␤ (ER␤) 1 in particular has been shown to be a critical regulator of many neurobiological functions. An important component of ER␤ signaling is requisite associations with intracellular coregulatory proteins. ...

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Section: Discussionmentioning

confidence: 99%

Age-dependent Effects of 17β-estradiol on the Dynamics of Estrogen Receptor β (ERβ) Protein–Protein Interactions in the Ventral Hippocampus

Mott

Pinceti

Rao

et al. 2014

Molecular & Cellular Proteomics

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“…Rapid neuroprotection by estradiol is partially mediated by G-protein-coupled receptor 30 (GPR30) and the subsequent downregulation of NMDA receptors (175). Interestingly, the neuroprotective effects of estradiol are sexually dimorphic and mediated by ERα (43). In a study of rat pups, pretreatment with 17β-estradiol protected female but not male cortical neurons from glutamate toxicity (43).…”

Section: Effects Of Reproductive Steroids On Biological Systems Implimentioning

confidence: 99%

“…Interestingly, the neuroprotective effects of estradiol are sexually dimorphic and mediated by ERα (43). In a study of rat pups, pretreatment with 17β-estradiol protected female but not male cortical neurons from glutamate toxicity (43). Estradiol regulates cellular energetics by improving mitochondrial respiratory efficiency and prevents oxygen-free radicals that are thought to adversely affect mitochondrial energetics in depression (102,103,170).…”

Section: Effects Of Reproductive Steroids On Biological Systems Implimentioning

confidence: 99%

Reproductive Steroid Regulation of Mood and Behavior

Schiller

Johnson

Abate

et al. 2016

Comprehensive Physiology

152

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In this article, we examine evidence supporting the role of reproductive steroids in the regulation of mood and behavior in women and the nature of that role. In the first half of the article, we review evidence for the following: (i) the reproductive system is designed to regulate behavior; (ii) from the subcellular to cellular to circuit to behavior, reproductive steroids are powerful neuroregulators; (iii) affective disorders are disorders of behavioral state; and (iv) reproductive steroids affect virtually every system implicated in the pathophysiology of depression. In the second half of the article, we discuss the diagnosis of the three reproductive endocrine-related mood disorders (premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression) and present evidence supporting the relevance of reproductive steroids to these conditions. Existing evidence suggests that changes in reproductive steroid levels during specific reproductive states (i.e., the premenstrual phase of the menstrual cycle, pregnancy, parturition, and the menopause transition) trigger affective dysregulation in susceptible women, thus suggesting the etiopathogenic relevance of these hormonal changes in reproductive mood disorders. Understanding the source of individual susceptibility is critical to both preventing the onset of illness and developing novel, individualized treatments for reproductive-related affective dysregulation. © 2016 American Physiological Society. Compr Physiol 6:1135-1160, 2016e.

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“…17βE 2 also reduces glutamate-induced death of cultured astrocytes [96] and immortalized mouse hippocampal neurons [97] in an ICI-sensitive manner, although the ER subtype mediating this protection was not identified. There is also an interesting report that a brief pretreatment with 17βE 2 or an ERα-selective agonist can protect female, but not male, cortical neurons from glutamate toxicity [98]. Studies in human neuroblastoma cells (SK-NM-C) challenged with a calcium ionophore also indicate that transfection with ERα, but not ERβ, confers neuroprotection [99].…”

Section: Role Of Erα In the Neuroprotective Effects Of Estrogensmentioning

confidence: 99%

Neuroprotection and Estrogen Receptors

Simpkins¹,

Singh²,

Brock³

et al. 2012

Neuroendocrinology

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This review is intended to assess the state of current knowledge on the role of estrogen receptors (ERs) in the neuroprotective effects of estrogens in models for acute neuronal injury and death. We evaluate the overall evidence that estrogens are neuroprotective in acute injury and critically assess the role of ERα, ERβ, GPR 30, and nonreceptor-mediated mechanisms in these robust neuroprotective effects of this ovarian steroid hormone. We conclude that all three receptors, as well as nonreceptor-mediated mechanisms can be involved in neuroprotection, depending on the model used, the level of estrogen administrated, and the mode of administration of the steroid. Also, the signaling pathways used by both ER-dependent and ER-independent mechanisms to exert neuroprotection are considered. Finally, further studies that are needed to parse out the relative contribution of receptor versus nonreceptor-mediated signaling are discussed.

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Roles of estrogen receptors alpha and beta in sexually dimorphic neuroprotection against glutamate toxicity

Cited by 47 publications

References 47 publications

Age-dependent Effects of 17β-estradiol on the Dynamics of Estrogen Receptor β (ERβ) Protein–Protein Interactions in the Ventral Hippocampus

Age-dependent Effects of 17β-estradiol on the Dynamics of Estrogen Receptor β (ERβ) Protein–Protein Interactions in the Ventral Hippocampus

Reproductive Steroid Regulation of Mood and Behavior

Neuroprotection and Estrogen Receptors

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