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Oestrogen as a neuroprotective hormone

Key Points

  • There is abundant experimental evidence that the sex hormone oestrogen might have neuroprotective actions. Observations in vivo and in vitro, as well as epidemiological studies, lend general support to this idea.

  • There are several possible mechanisms to account for the neuroprotective actions of oestrogen. In the simplest scenario, oestrogen receptors, which are transcription factors, might act directly on genes that code for proteins that modulate nerve-cell survival, regulating their expression. These proteins might enhance neurotrophic support, suppress apoptosis and affect neuronal structure.

  • The neuroprotective action of oestrogen could also depend on non-classical actions of this neurohormone. Indeed, oestrogen can interact with intracellular signalling pathways that are directly linked to the control of neuronal survival, such as the mitogen-activated protein kinase (MAPK) pathway, cyclic-AMP-responsive-element-binding protein (CREB) and phosphatidylinositol 3-kinase (PI3K). In addition, the chemical structure of oestrogen enables it to act as a free-radical scavenger, preventing oxidative damage.

Abstract

In addition to its role as a sex hormone, oestrogen affects the structure and function of the nervous system. Oestrogen receptors are expressed in brain regions that are involved in sex differentiation and maturation. But in addition to its well-known effects, oestrogen also has important neuroprotective actions that are both dependent and independent of a nuclear oestrogen-receptor activity. Furthermore, oestrogen can interact with neuroprotective intracellular signalling pathways and is itself a neuroprotective antioxidant. Understanding the mechanisms of oestrogen action will be crucial to determine its potential as a therapeutic agent, particularly in the elderly.

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Figure 1: Chemical structure of oestrogen and related naturally occurring molecules.
Figure 2: Oestrogen protects against nerve-cell death.
Figure 3: The oestrogen receptor belongs to the superfamily of nuclear receptors.
Figure 4: Expression of ERα and ERβ in the rodent brain.
Figure 5: Simplified model of the classical and non-classical modes of oestrogen action.
Figure 6: Some possible modes of oestrogen-mediated neuroprotection.

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Acknowledgements

I thank S. Goodenough, N. Bayatti and D. Manthey for fruitful discussions. The work of my laboratory is supported in part by grants from the Deutsche Forschungsgemeinschaft and the European Union.

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DATABASES

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ERα

ERβ

Medscape DrugInfo

oestrone

raloxifene

tamoxifen

OMIM

Alzheimer's disease

Parkinson's disease

FURTHER INFORMATION

Encyclopedia of Life Sciences

ageing and the brain

Alzheimer disease

hormones and behaviour

oestrogens, mood and cognition

Parkinson disease

Glossary

REPERFUSION DAMAGE

The tissue damage that occurs after an episode of ischaemia, not as a result of lack of blood, but as a consequence of the return of blood to the affected region.

HILUS

A subdivision of the hippocampus that is rich in interneurons. It is located between the CA3 region and the dentate gyrus.

NUCLEUS BASALIS OF MEYNERT

A telencephalic structure that provides most of the acetylcholine to the cerebral cortex.

INVERTED REPEAT

A nucleotide sequence that is found at two sites on the same DNA segment, but with opposite orientations.

PALINDROMIC SEQUENCE

A sequence of nucleotides that reads the same regardless of direction.

NEUROFILAMENT

A type of intermediate filament that is found only in neurons and serves as a cytoskeletal element that supports the axonal cytoplasm.

SH DOMAINS

Src-homology domains are involved in interactions with phosphorylated tyrosine residues on other proteins (SH2 domains) or with proline-rich sections of other proteins (SH3 domains).

FK506

A metabolic product of the fungus Streptomyces tsukabaensis that is commonly used as an immunosupressant agent. FK506 has a binding protein that, when bound to the drug, inhibits the phosphatase calcineurin.

CAVEOLAE

Specialized rafts that contain the protein caveolin and form a flask-shaped, cholesterol-rich invagination of the plasma membrane, which might mediate the uptake of some extracellular materials and are probably involved in cell signalling.

EXPRESSION PROFILING

The use of DNA microarrays to determine the expression level of thousands of genes simultaneously.

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Behl, C. Oestrogen as a neuroprotective hormone. Nat Rev Neurosci 3, 433–442 (2002). https://doi.org/10.1038/nrn846

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