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      Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury

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          Abstract

          Traumatic brain injury (TBI) is a serious public health problem. It may result in severe neurological disabilities and in a variety of cellular metabolic alterations for which available therapeutic strategies are limited. In the last decade, the use of estrogenic compounds, which activate protective mechanisms in astrocytes, has been explored as a potential experimental therapeutic approach. Previous works have suggested estradiol (E2) as a neuroprotective hormone that acts in the brain by binding to estrogen receptors (ERs). Several steroidal and nonsteroidal estrogenic compounds can imitate the effects of estradiol on ERs. These include hormonal estrogens, phytoestrogens and synthetic estrogens, such as selective ER modulators or tibolone. Current evidence of the role of astrocytes in mediating protective actions of estrogenic compounds after TBI is reviewed in this paper. We conclude that the use of estrogenic compounds to modulate astrocytic properties is a promising therapeutic approach for the treatment of TBI.

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          Most cited references222

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          Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury.

          Astroglial scars surround damaged tissue after trauma, stroke, infection, or autoimmune inflammation in the CNS. They are essential for wound repair, but also interfere with axonal regrowth. A better understanding of the cellular mechanisms, regulation, and functions of astroglial scar formation is fundamental to developing safe interventions for many CNS disorders. We used wild-type and transgenic mice to quantify and dissect these parameters. Adjacent to crush spinal cord injury (SCI), reactive astrocytes exhibited heterogeneous phenotypes as regards proliferation, morphology, and chemistry, which all varied with distance from lesions. Mature scar borders at 14 d after SCI consisted primarily of newly proliferated astroglia with elongated cell processes that surrounded large and small clusters of inflammatory, fibrotic, and other cells. During scar formation from 5 to 14 d after SCI, cell processes deriving from different astroglia associated into overlapping bundles that quantifiably reoriented and organized into dense mesh-like arrangements. Selective deletion of STAT3 from astroglia quantifiably disrupted the organization of elongated astroglia into scar borders, and caused a failure of astroglia to surround inflammatory cells, resulting in increased spread of these cells and neuronal loss. In cocultures, wild-type astroglia spontaneously corralled inflammatory or fibromeningeal cells into segregated clusters, whereas STAT3-deficient astroglia failed to do so. These findings demonstrate heterogeneity of reactive astroglia and show that scar borders are formed by newly proliferated, elongated astroglia, which organize via STAT3-dependent mechanisms to corral inflammatory and fibrotic cells into discrete areas separated from adjacent tissue that contains viable neurons.
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            Ageing and neuronal vulnerability.

            Everyone ages, but only some will develop a neurodegenerative disorder in the process. Disease might occur when cells fail to respond adaptively to age-related increases in oxidative, metabolic and ionic stress, thereby resulting in the accumulation of damaged proteins, DNA and membranes. Determinants of neuronal vulnerability might include cell size and location, metabolism of disease-specific proteins and a repertoire of signal transduction pathways and stress resistance mechanisms. Emerging evidence on protein interaction networks that monitor and respond to the normal ageing process suggests that successful neural ageing is possible for most people, but also cautions that cures for neurodegenerative disorders are unlikely in the near future.
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              New roles for astrocytes: redefining the functional architecture of the brain.

              Astrocytes have traditionally been considered ancillary, satellite cells of the nervous system. However, work over the past decade has revealed that they interact with the vasculature to form a gliovascular network that might organize not only the structural architecture of the brain but also its communication pathways, activation, thresholds and plasticity. The net effect is that astroglia demarcate gray matter regions, both cortical and subcortical, into functional compartments whose internal activation thresholds and external outputs are regulated by single glial cells. The array of these astrocyte-delimited microdomains along the capillary microvasculature allows the formation of higher-order gliovascular units, which serve to match local neural activity and blood flow while regulating neuronal firing thresholds through coordinative glial signaling. By these means, astrocytes might establish the functional as well as the structural architecture of the adult brain.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2019
                February 2019
                04 November 2018
                : 108
                : 2
                : 142-160
                Affiliations
                [_a] aDepartamento de Nutrición y Bioquímica, Facultad de Ciencias Pontificia Universidad Javeriana, Bogotá, Colombia
                [_b] bUniversidad San Sebastián, Fac. Cs de la Salud, Concepción, Chile
                [_c] cResearch and Development Service, Bay Pines VA Healthcare System, Bay Pines, Florida, USA
                [_d] dKing Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
                [_e] eBiotechnology Research Center, Pharmaceutical technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
                [_f] fNeurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
                [_g] gSchool of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
                [_h] hInstituto Cajal, CSIC, Madrid, Spain
                [_i] iCentro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
                Author notes
                *George E. Barreto, PhD, Departamento de Nutrición y Bioquímica, Facultad de Ciencias Pontificia Universidad Javeriana, Cra 7 40-62, Bogotá D.C. (Colombia), E-Mail gsampaio@javeriana.edu.co, gesbarreto@gmail.com, , Luis Miguel Garcia-Segura, PhD, Instituto Cajal, CSIC, Madrid (Spain), E-Mail lmgs@cajal.csic.es
                Author information
                https://orcid.org/0000-0002-6644-1971
                Article
                495078 Neuroendocrinology 2019;108:142–160
                10.1159/000495078
                30391959
                cc77c321-7b43-49f9-a9bb-f44e1ba423c6
                © 2018 S. Karger AG, Basel

                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
                : 24 July 2018
                : 02 November 2018
                Page count
                Figures: 2, Tables: 4, Pages: 19
                Categories
                At the Cutting Edge

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Traumatic brain injury,Neuroprotection,Estrogenic compounds,Astrocytes

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