17β-Estradiol – A New Modulator of Neuroglobin Levels in Neurons: Role in Neuroprotection against H 2 O 2 -Induced Toxicity

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Abstract

Although discovered in 2000, neuroglobin (Ngb) functions are still uncertain. A contribution to the role played by Ngb in neurons could certainly derive from the identification of Ngb endogenous modulators. Here, we evaluate the possibility that Ngb could be regulated by 17β-estradiol (E2) signaling in both SK-N-BE human neuroblastoma cell line and mouse hippocampal neurons. 1 n M E2 rapidly induced a 300% increase in Ngb levels in both models. The E2 effect was specific, being not induced by testosterone or dihydrotestosterone. The E2-induced Ngb increase requires estrogen receptor (ER) β, but not ERα, as evaluated by the mimetic effect of ERβ-specific agonist DPN and by the blockage of E2 effect in ERβ-silenced SK-N-BE cells. Furthermore, both rapid (15 min) ERβ-dependent activation of p38/MAPK and transcriptional ERβ activity were required for the estrogenic regulation of Ngb. Finally, E2 exerted a protective effect against H2O2-induced neuroblastoma cell death which was completely prevented in Ngb-silenced cells. Overall, these data suggest that Ngb is part of the E2 signaling mechanism that is activated to exert protective effects against H2O2-induced neurotoxicity.

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Most cited references 69

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Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines.

Glenda Gillies, Simon McArthur (2010)

The classic view of estrogen actions in the brain was confined to regulation of ovulation and reproductive behavior in the female of all mammalian species studied, including humans. Burgeoning evidence now documents profound effects of estrogens on learning, memory, and mood as well as neurodevelopmental and neurodegenerative processes. Most data derive from studies in females, but there is mounting recognition that estrogens play important roles in the male brain, where they can be generated from circulating testosterone by local aromatase enzymes or synthesized de novo by neurons and glia. Estrogen-based therapy therefore holds considerable promise for brain disorders that affect both men and women. However, as investigations are beginning to consider the role of estrogens in the male brain more carefully, it emerges that they have different, even opposite, effects as well as similar effects in male and female brains. This review focuses on these differences, including sex dimorphisms in the ability of estradiol to influence synaptic plasticity, neurotransmission, neurodegeneration, and cognition, which, we argue, are due in a large part to sex differences in the organization of the underlying circuitry. There are notable sex differences in the incidence and manifestations of virtually all central nervous system disorders, including neurodegenerative disease (Parkinson's and Alzheimer's), drug abuse, anxiety, and depression. Understanding the cellular and molecular basis of sex differences in brain physiology and responses to estrogen and estrogen mimics is, therefore, vitally important for understanding the nature and origins of sex-specific pathological conditions and for designing novel hormone-based therapeutic agents that will have optimal effectiveness in men or women.

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Structure-function relationship of estrogen receptor alpha and beta: impact on human health.

Alessio Bocedi, Rosa Anna Maria Marino, Paolo Ascenzi (2006)

17Beta-estradiol (E2) controls many aspects of human physiology, including development, reproduction and homeostasis, through regulation of the transcriptional activity of its cognate receptors (ERs). The crystal structures of ERs with agonists and antagonists and the use of transgenic animals have revealed much about how hormone binding influences ER conformation(s) and how this conformation(s), in turn, influences the interaction of ERs with co-activators or co-repressors and hence determines ER binding to DNA and cellular outcomes. This information has helped to shed light on the connection between E2 and the development or progression of numerous diseases. Current therapeutic strategy in the treatment of E2-related pathologies relies on the modulation of ER trancriptional activity by anti-estrogens; however, data accumulated during the last five years reveal that ER activities are not only restricted to the nucleus. ERs are very mobile proteins continuously shuttling between protein targets located within various cellular compartments (e.g., membrane, nucleus). This allows E2 to generate different and synergic signal transduction pathways (i.e., non-genomic and genomic) which provide plasticity for cell response to E2. Understanding the structural basis and the molecular mechanisms by which ER transduce E2 signals in target cells will allow to create new pharmacologic therapies aimed at the treatment of a variety of human diseases affecting the cardiovascular system, the reproductive system, the skeletal system, the nervous system, the mammary gland, and many others.

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Estrogen signaling: a subtle balance between ER alpha and ER beta.

Jason Matthews, Jan-Åke Gustafsson (2003)

The biological actions of estrogens are mediated by estrogen binding to one of two specific estrogen receptors (ERs) ERalpha and ERbeta, which belong to the nuclear receptor superfamily, a family of ligand-regulated transcription factors. ERalpha and ERbeta are products of different genes and exhibit tissue- and cell-type specific expression. The characterization of mice lacking ERalpha, or ERbeta, or both has revealed that both receptor subtypes have overlapping but also unique roles in estrogen-dependent action in vivo. Additionally, ERalpha and ERbeta have different transcriptional activities in certain ligand, cell-type, and promoter contexts. Both receptors, however, are coexpressed in a number of tissues and form functional heterodimers. The biological roles of ERalpha /beta heterodimers in the presence of each respective homodimer are unknown. When coexpressed, ERbeta exhibits an inhibitory action on ERalpha -mediated gene expression and in many instances opposes the actions of ERalpha. A number of ERalpha and ERbeta isoforms have also been described, many of which alter estrogen-mediated gene expression. Uncovering the molecular mechanisms regulating the expression of both ERs, and how ERalpha and ERbeta directly or indirectly affect each other's function are paramount to understanding the cellular and biological events of estrogen-mediated gene regulation in normal and diseased tissues.

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Author and article information

Journal

Journal ID (publisher-id): NSG

Journal ID (nlm-ta): Neurosignals

Journal ID (doi): 10.1159/issn.1424-862X

Title: Neurosignals

Publisher: S. Karger AG

ISSN (Print): 1424-862X

ISSN (Electronic): 1424-8638

Publication date Subscription-year: 2010

Publication date (Print): March 2011

Publication date (Electronic): 18 February 2011

Volume: 18

Issue: 4

Pages: 223-235

Affiliations

^aDepartment of Biology and ^bInterdepartmental Laboratory of Electron Microscopy, University Roma Tre, Rome, Italy; ^cInstituto Cajal, CSIC, Madrid, Spain

Author notes

*Maria Marino, Department of Biology, University Roma Tre, Viale Guglielmo Marconi 446, IT–00146 Rome (Italy), Tel. +39 06 57 336 345, E-Mail m.marino@uniroma3.it

Article

Publisher ID: 323906 Other ID: Neurosignals 2010;18:223–235

DOI: 10.1159/000323906

PubMed ID: 21335947

SO-VID: 7af07194-7f89-42f1-87e0-5b373a4075bd

License:

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 01 November 2010

Date accepted : 28 December 2010

Page count

Figures: 6, Pages: 13

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