Review Article | Published:

The neuroprotective actions of oestradiol and oestrogen receptors

Nature Reviews Neuroscience volume 16, pages 1729 (2015) | Download Citation

Abstract

Hormones regulate homeostasis by communicating through the bloodstream to the body's organs, including the brain. As homeostatic regulators of brain function, some hormones exert neuroprotective actions. This is the case for the ovarian hormone 17β-oestradiol, which signals through oestrogen receptors (ERs) that are widely distributed in the male and female brain. Recent discoveries have shown that oestradiol is not only a reproductive hormone but also a brain-derived neuroprotective factor in males and females and that ERs coordinate multiple signalling mechanisms that protect the brain from neurodegenerative diseases, affective disorders and cognitive decline.

Key points

  • Oestradiol is both a sex steroid hormone and a neurosteroid that is locally synthesized in the brain. Both hormonal oestradiol and brain-derived oestradiol are neuroprotective.

  • Oestradiol synthesis in the brain is rapidly regulated in neurons by synaptic activity. In turn, brain-derived oestradiol regulates synaptic plasticity, adult neurogenesis, reproductive behaviour, aggressive behaviour, pain processing, affect and cognition.

  • Under pathological conditions, the expression of aromatase, the enzyme that produces oestradiol, is enhanced in neurons and induced de novo in astrocytes as an endogenous neuroprotective mechanism. Inhibition or silencing of brain aromatase increases gliosis and neurodegeneration after brain injury.

  • The neuroprotective actions of oestradiol are mediated by two oestrogen receptors (ERs) located in the cell nucleus, ERα and ERβ, and by ERs located in the membrane, including ERα, ERβ, G protein-coupled ER and Gαq protein-coupled ER.

  • The ERs coordinate various neuroprotective signalling mechanisms, some of which are complementary and some of which are redundant. These include the regulation of transcription by nuclear ERs and the regulation of the activity of different kinases by membrane ERs.

  • Membrane and intracellular ERs also contribute to the interaction of oestradiol signalling with the signalling of other neuroprotective factors, such as brain-derived neurotrophic factor, insulin-like growth factor 1, WNT and Notch.

  • Further studies are necessary to determine the role of neuronal and non-neuronal cells in the coordination of oestradiol-mediated neuroprotective signalling mechanisms. The influence of sex and age on these mechanisms should also be studied.

  • A promising research direction aims to determine the role of metabolic homeostatic regulation in the protective actions of oestradiol, particularly in chronic neurodegenerative diseases.

  • Further research should also explore alternatives to oestradiol therapy, including new ligands for ERs and modulators of brain oestradiol synthesis.

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Acknowledgements

The authors thank M. Garcia-Diaz, Stony Brook University School of Medicine, New York, USA, for critical reading of the manuscript. The authors acknowledge support from Ministerio de Economía y Competitividad, Spain (BFU2011-30217-C03-01).

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Affiliations

  1. Instituto Cajal, Consejo Superior de Investigaciones Científicas, E-28002 Madrid, Spain.

    • Maria-Angeles Arevalo
    •  & Luis M. Garcia-Segura
  2. Department of Cell Biology, Faculty of Biology, Universidad Complutense, E-28040 Madrid, Spain.

    • Iñigo Azcoitia

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  2. Search for Iñigo Azcoitia in:

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Luis M. Garcia-Segura.

Glossary

Hormone

A cellular secretion released into circulation that targets multiple cell types in multiple organs.

Autocrine factor

A substance released by a cell that targets nearby cells of the same type.

Paracrine factor

A substance released by a cell that targets nearby cells of multiple types.

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Antisense oligonucleotides

Oligonucleotides with a sequence that is complementary to the mRNA of a given molecule, which can be used to block its translation. The subsequent temporary elimination of the protein of interest often provides useful information on its biological function.

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Proteins that activate or repress transcriptional activity by binding to transcription factors. Co-activators and co-repressors are unable to bind to DNA by themselves.

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Submicrodomains of the plasma membrane that are enriched in sphingolipids and cholesterol and are thought to serve as a signalling platform.

Phosphoinositide 3-kinase (PI3K) signalling pathway

A cell survival pathway that is activated by receptor tyrosine kinases. The activation of PI3K results in the phosphorylation and activation of the kinase AKT and in the subsequent phosphorylation and inhibition of glycogen synthase kinase-3β.

Neurovascular unit

A complex multicellular functional unit of the CNS comprising vascular cells, glial cells and neurons, which together determine CNS activities and responses in health and disease.

Coincidence signal detector

A mechanism that detects the temporal coincidence of multiple signals.

Positron emission tomography

A medical imaging technique that uses injected radiolabelled tracer compounds, in conjunction with mathematical reconstruction methods, to produce a three-dimensional image, or map, of functional processes in the body (such as glucose metabolism, blood flow or receptor distributions).

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