Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2002 Jun;4(2):149-61.

Estrogen and Neuroprotection: From Clinical Observations to Molecular Mechanisms

Affiliations
Free PMC article

Estrogen and Neuroprotection: From Clinical Observations to Molecular Mechanisms

Dena B Dubal et al. Dialogues Clin Neurosci. .
Free PMC article

Abstract

We now appreciate that estrogen is a pleiotropic gonadal steroid that exerts profound effects on the plasticity and cell survival of the adult brain. Over the past century, the life span of women has increased, but the age of the menopause remains constant. This means that women may now live over one third of their lives in a hypoestrogenic, postmenopausal state. The impact of prolonged hypoestrogenicity on the brain is now a critical health concern as we realize that these women may suffer an increased risk of cognitive dysfunction and neurodegeneration due to a variety of diseases. Accumulating evidence from both clinical and basic science studies indicates that estrogen exerts critical protective actions against neurodegenerative conditions such as Alzheimer's disease and stroke. Here, we review the discoveries that comprise our current understanding of estrogen action against neurodegeneration. These findings carry far-reaching possibilities for improving the quality of life in our aging population.

Actualmente nosotros sabemos que los estrógenos son esteroides gonadales pleiotrópicos que ejercen efectos significativos en la plasticidad y en la sobrevida celular del cerebro adulto. Durante el siglo pasado la duración de la vida de las mujeres ha aumentado, pero la edad de la menopausia se ha mantenido constante. Esto signífica que ahora las mujeres pueden vivir más de un tercio de sus vidas en un estado hipoestrogénico postmenopáusico. El impacto en el cerebro del hipoestrogenismo prolongado constituye ahora una preocupación crítica de salud ya que nos damos cuenta que estas mujeres pueden tener un aumento del ríesgo de disfunción cognitiva y de neurodegeneración debido a una variedad de enfermedades. La evidencia que se ha acumulado tanto de los estudios clínicos como de ciencias básicas índica que los estrógenos ejercen acciones protectoras críticas ante condíciones neurodegenerativas como la enfermedad de Alzheimer y los accidentes vasculares cerebrales. En este artículo nosotros revisamos los descubrímientos que engloban nuestra comprensión actual de la acción de los estrógenos contra la neurodegeneración. Estos hallazgos conducen a posibilidades de gran alcance para mejorar la calidad de vida en nuestra población que envejece.

Nous savons maintenant que les estrogènes sont des stéroïdes gonadiques pléiotropes qui exercent d'importants effets sur la plasticité et la survie cellulaire du cerveau de l'adulte. Si l'espérance de vie des femmes a augmenté au siècle dernier, l'âge de la ménopause, quant à lui, reste constant. Cela signifie que les femmes peuvent maintenant passer plus d'un tiers de leur vie dans un climat postménopausique, hypoestrogénique. L'impact sur le cerveau d'une hypoestrogénicité prolongée est devenu un souci de santé préoccupant car nous réalisons que ces femmes peuvent être confrontées à un risque accru de dysfonctionnement cognitif et de neurodégénérescence secondaires à de nombreuses maladies. L'accumulation des constatations issues des études scientifiques cliniques et fondamentales indique que les estrogènes exercent des actions protectrices cruciales contre les pathologies neurodégénératives telles que la maladie d'Alzheimer et l'accident vasculaire cérébral. Nous passons ici en revue les découvertes qui constituent nos connaissances actuelles sur l'action des estrogènes contre la neurodégénérescence. Ces découvertes ouvrent la voie à des possibilités d'une portée considérable pour améliorer la qualité de vie de notre population vieillissante.

Keywords: Alzheimer's disease; cerebral ischemia; cognition, brain injury; estradiol; estrogen; estrogen replacement therapy; menopause; neuroprotection; stroke.

Figures

Figure 1.
Figure 1.. Endogenous estrogen may decrease the risk for stroke. Prior to the menopause, women appear to be protected against the occurrence of stroke, compared with age-matched men (left). However, this protection is lost at some time after the menopause (right), suggesting that endogenous estrogen may play a protective role against stroke. Data modified from the American Heart Association (2001).
Figure 2.
Figure 2.. Physiological levels of estradiol decrease ischemic brain damage following stroke injury. Representative coronal sections obtained from oil-treated (left) and estradiol-treated (right) rat brains collected 24 h after the onset of ischemia and stained with hemotoxylin and eosin. Ischemic injury, produced by permanent middle cerebral artery occlusion, appears unstained and is distributed across the cerebral cortex and striatum. Pretreatment with low levels of estradiol dramatically decreases the extent of stroke injury, compared with oil-treated controls.
Figure 3.
Figure 3.. Estrogen receptors (ERs) act through traditional and novel mechanisms. This diagram illustrates ERs in their classical roles as transcription factors and in their newfound roles as components of signal transduction pathways. As transcription factors, ERs bind estradiol, dimerize, and then translocate to the nucleus. In the nucleus, ERs bind to estrogen-responsive elements in the promoters of target genes to induce or to suppress transcription. Cofactors can modulate the ER-DNA interactions to either amplify or diminish transcription. In addition to gene transactivation, ERs may also activate signal transduction pathways. For example, estradiol stimulates adenyly! cyclase (AC), one of several ways that it increases mitogen-activated protein kinase (MAPK) phosphorylation. Further, estradiol stimulates phosphoinositol-3-kinase (PI3K), which increases Akt (protein kinase B) phosphorylation. These effects on signal transduction may turn key proteins on or off, or ultimately induce genomic actions.
Figure 4.
Figure 4.. Estrogen receptor-α(ERα) is critical in estradiol-mediated protection of the brain following stroke injury. Estradiol (E) reduces ischemic infarct in both wildtype mice, WT (A) and WT (B), compared with corresponding oil-treated controls (n=6-10/group) (*P<0.02). Estradiol fails to protect in ERα knock-out (ERαKO) mice, compared with oil-treated controls (n=1 3/group) (A), but continues to protect in (B) ERβKO mice, compared with oil-treated controls (n=8-9/group) (*P<0.02). Values represent means±SE. Reproduced from reference 140: Dubai DB, Zhu B, Yu B, et al. Estrogen receptor-ot, not -3, is a critical link in estradiol-mediated protection against brain injury. Proc Natl Acad Sci U S A. 2001;98:1952-1957. Copyright © 2001, National Academy of Sciences, USA.

Similar articles

See all similar articles

Cited by 10 articles

See all "Cited by" articles

References

    1. vom Saal FS., Finch CE., Nelson JF. Natural history and mechanisms of reproductive aging in humans, laboratory rodents, and other selected vertebrates. In: Knobil E, Neill JD, eds. The Physiology of Reproduction. New York, NY: Raven Press; 1994:1213–1314.
    1. Wise PM. New understanding of the complexity of the menopause and challenges for the future. In: Bellino FL, ed. Proceedings of the International Symposium on the Biology of the Menopause. Norwell, Mass: Springer; 2000:1–8.
    1. Speroff L. Postmenopausal hormone therapy and breast cancer. Obstet Gynecol. 1996;87:44S–53S. - PubMed
    1. Hammond CB. Menopause and hormone replacement therapy: an overview. Obstet Gynecol. 1996;87:2S–15S. - PubMed
    1. Lindsay R. The menopause and osteoporosis. Obstet Gynecol. 1996;87:16S–19S. - PubMed

LinkOut - more resources

Feedback