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The neuroprotective actions of oestradiol and oestrogen receptors

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.

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.

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Figure 1: Neuroprotective actions of brain aromatase.
Figure 2: Oestradiol activates multiple neuroprotective signalling mechanisms.
Figure 3: Redundant neuroprotective signalling elicited by oestrogen receptors.
Figure 4: Oestradiol mediates indirect regulation of other neuroprotective signalling pathways.

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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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Arevalo, MA., Azcoitia, I. & Garcia-Segura, L. The neuroprotective actions of oestradiol and oestrogen receptors. Nat Rev Neurosci 16, 17–29 (2015). https://doi.org/10.1038/nrn3856

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