The neuroprotective actions of oestradiol and oestrogen receptors

Arévalo, María Ángeles; Azcoitia, Íñigo; Garcia-Segura, Luis Miguel

doi:10.1038/nrn3856

Cited by 360 publications

(346 citation statements)

References 187 publications

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“…Estrogen receptor-α (ERα) and ERβ are a subclass of the nuclear receptor superfamily that function as estrogendependent TFs. Estrogens exert neuroprotective actions by signaling through ERs that are widely distributed in the male and female brain (94). Estradiol is not only a reproductive hormone but also a brain-derived neuroprotective factor in both males and females that enables ERs to coordinate multiple signaling mechanisms that protect the brain from neurodegenerative diseases.…”

Section: Antiinflammatory and Tissue-supportive Mediatorsmentioning

confidence: 99%

Transcriptional control of microglia phenotypes in health and disease

Holtman¹,

Skola²,

Glass³

2017

Journal of Clinical Investigation

175

156

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Section: Antiinflammatory and Tissue-supportive Mediatorsmentioning

confidence: 99%

Transcriptional control of microglia phenotypes in health and disease

Holtman¹,

Skola²,

Glass³

2017

Journal of Clinical Investigation

175

156

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“…Circulating E2 levels are known to fluctuate during development and puberty, as well as during the menstrual cycle. After menopause, however, circulating E2 levels decline precipitously (4). Relative to men, women are "protected" against stroke until the years of menopause.…”

mentioning

confidence: 99%

“…Both subtypes are expressed in the brain and have been shown to mediate various neural actions of E2, including neuroprotection (4,(12)(13)(14). For example, ER genomic actions have been shown to contribute to increased expression of the antiapoptotic gene, bcl-2, and the antiapoptotic prosurvival factor, survivin, which can contribute to E2 neuroprotective effects (11,15,16).…”

mentioning

confidence: 99%

“…Recent evidence suggests that E2 also exerts "rapid signaling" in the brain via interaction with extranuclear ER, which can lead to regulation of kinase activation and ion channels (17,18). ER "extranuclear" signaling has been suggested to contribute to E2 neuroprotective effects by facilitating the rapid activation of extracellular signal-regulated kinases (ERKs) and prosurvival serine threonine kinase Akt (4,(19)(20)(21)(22). Furthermore, E2 also interacts with nonclassical ERs such as G protein-coupled estrogen receptor, which can also contribute to activation of ERK and PI3K (4,23).…”

mentioning

confidence: 99%

“…ER "extranuclear" signaling has been suggested to contribute to E2 neuroprotective effects by facilitating the rapid activation of extracellular signal-regulated kinases (ERKs) and prosurvival serine threonine kinase Akt (4,(19)(20)(21)(22). Furthermore, E2 also interacts with nonclassical ERs such as G protein-coupled estrogen receptor, which can also contribute to activation of ERK and PI3K (4,23). Transcriptional activity of E2-bound ERs is regulated by several coregulatory proteins that associate with the ER in response to E2 binding (24).…”

mentioning

confidence: 99%

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Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain

Sareddy

Zhang

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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17-β estradiol (E2) has been implicated as neuroprotective in a variety of neurodegenerative disorders. However, the underlying mechanism remains unknown. Here, we provide genetic evidence, using forebrain-specific knockout (FBKO) mice, that proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), an estrogen receptor coregulator protein, is essential for the extranuclear signaling and neuroprotective actions of E2 in the hippocampal CA1 region after global cerebral ischemia (GCI). E2-mediated extranuclear signaling (including activation of extracellular signal-regulated kinase and Akt) and antiapoptotic effects [such as attenuation of JNK signaling and increase in phosphorylation of glycogen synthase kinase-3β (GSK3β)] after GCI were compromised in PELP1 FBKO mice. Mechanistic studies revealed that PELP1 interacts with GSK3β, E2 modulates interaction of PELP1 with GSK3β, and PELP1 is a novel substrate for GSK3β. RNA-seq analysis of control and PELP1 FBKO mice after ischemia demonstrated alterations in several genes related to inflammation, metabolism, and survival in PELP1 FBKO mice, as well as a significant reduction in the activation of the Wnt/ β-catenin signaling pathway. In addition, PELP1 FBKO studies revealed that PELP1 is required for E2-mediated neuroprotection and for E2-mediated preservation of cognitive function after GCI. Collectively, our data provide the first direct in vivo evidence, to our knowledge, of an essential role for PELP1 in E2-mediated rapid extranuclear signaling, neuroprotection, and cognitive function in the brain.he steroid hormone, 17β-estradiol (E2), exerts multiple actions in the brain, including regulation of synaptic plasticity, neurogenesis, reproductive behavior, and cognition. E2 has also been implicated to serve as an important neuroprotective factor in a variety of neurodegenerative disorders, including stroke and Alzheimer's disease (1-3). The main source of E2 synthesis in females is the ovary. Circulating E2 levels are known to fluctuate during development and puberty, as well as during the menstrual cycle. After menopause, however, circulating E2 levels decline precipitously (4). Relative to men, women are "protected" against stroke until the years of menopause. However, after menopause, women exhibit a significantly higher disability and fatality rate compared with men (5-7). Intriguingly, the higher risk and poorer outcome of stroke in postmenopausal women parallels the falling E2 levels that occur after menopause (7,8). Furthermore, exogenous administration of E2 significantly reduces the infarct volume in cortex and hippocampus after focal and global cerebral ischemia (GCI) in various animal models, and female animals exhibit reduced neural damage compared with young adult males after brain injury (1, 9-11). Taken as a whole, these studies suggest E2 functions as an important neuroprotective factor. However, the molecular mechanisms by which E2 exerts its neuroprotective effects remain unclear.E2 signaling is thought to be primarily mediated by the classical...

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Association of Age at Menopause and Duration of Reproductive Period With Depression After Menopause

et al. 2016

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IMPORTANCE Estrogens have neuroprotective and antidepressive effects; however, associations between indices of reduced endogenous estrogens and risk for postmenopausal depression have not been systematically explored. OBJECTIVE To investigate the association of age at menopause and the duration of the reproductive period with the risk for depression among postmenopausal women with naturally occurring menopause. DATA SOURCES A search strategy for use of MEDLINE was developed (through January 1, 2015) using the key terms menopause, climacteric, reproductive period, depression, and mood disorders. References of included studies and reviews were also screened; authors were contacted to maximize synthesized evidence. STUDY SELECTION A total of 12 323 articles, without language restriction, were screened by pairs of reviewers to identify observational studies related to the study hypothesis; 14 studies were eligible for meta-analysis. DATA EXTRACTION AND SYNTHESIS Pairs of reviewers independently extracted information on study design and type of analysis by participants' characteristics and methods of depression ascertainment. Study quality was assessed using the Newcastle-Ottawa Scale, and fixed-or random-effects models were implemented. MAIN OUTCOMES AND MEASURES Pooled-effect estimates for depression, defined by psychiatric evaluation or validated instruments, by age at menopause and duration of the reproductive period. RESULTS The 14 studies included in the meta-analysis represented 67 714 women. An inverse association (reported as odds ratio [OR]; 95% CI of 2-year increments) with depression in postmenopausal women was shown for increasing age at menopause (0.98; 0.96-0.99 [67 434 unique participants; 13 studies]) and duration of the reproductive period (0.98; 0.96-0.99 [54 715 unique participants; 5 studies]). Menopause at age 40 or more years compared with premature menopause was associated with a 50% decreased risk for depression (3033 unique participants; 4 studies). Pooling of studies examining severe depression showed a 5% decrease in risk of severe depression with increasing (2-year increment) age at menopause (52 736 unique participants; 3 studies); sensitivity analysis of studies controlling for past depression revealed similar results for age at menopause (0.98; 0.96-1.00 [48 894 unique participants; 3 studies). No heterogeneity or publication bias was evident in the main analyses. CONCLUSIONS AND RELEVANCE Longer exposure to endogenous estrogens, expressed as older age at menopause and longer reproductive period, is associated with a lower risk of depression in later life. Identifying women at higher risk for depression due to early menopause who could benefit from psychiatric intervention or estrogen-based therapies could be useful in the clinical setting.

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The neuroprotective actions of oestradiol and oestrogen receptors

Cited by 360 publications

References 187 publications

Transcriptional control of microglia phenotypes in health and disease

Transcriptional control of microglia phenotypes in health and disease

Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain

Association of Age at Menopause and Duration of Reproductive Period With Depression After Menopause

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