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      Estrogens as Neuroprotectants against Ischemic Stroke

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          Abstract

          Estrogens have proven vasoprotective properties against atherosclerosis that depend on the direct effect on vascular smooth muscle and endothelium and on systemic actions that imply serum lipids, coagulation and fibrinolytic cascades, vasoactive proteins and antioxidant systems. They also have neuroprotective effects against cerebral ischemia that include antioxidant and anti-inflammatory effects, modulation of protein synthesis, inhibition of apoptosis and trophic effects and preservation of microvascular blood flow in the ischemic area. Estrogenic actions depend on activation of specific estrogen receptors that modulate gene expression and produce long-term effects on vascular endothelial and smooth muscle cells, neurons and glia, on interaction with plasma membrane sites that produce rapid non-genomic actions and also on receptor-independent mechanisms. This paper reviews what it is known about the mechanisms underlying the vaso- and neuroprotective effects of estrogens. Experimental and clinical evidences of such protective effects are also discussed. Therapeutical implications for stroke prevention and treatment derived from the available evidence are considered.

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          Most cited references 39

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          Effects of estrogen replacement on the progression of coronary-artery atherosclerosis.

          Heart disease is a major cause of illness and death in women. To understand better the role of estrogen in the treatment and prevention of heart disease, more information is needed about its effects on coronary atherosclerosis and the extent to which concomitant progestin therapy may modify these effects. We randomly assigned a total of 309 women with angiographically verified coronary disease to receive 0.625 mg of conjugated estrogen per day, 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate per day, or placebo. The women were followed for a mean (+/-SD) of 3.2+/-0.6 years. Base-line and follow-up coronary angiograms were analyzed by quantitative coronary angiography. Estrogen and estrogen plus medroxyprogesterone acetate produced significant reductions in low-density lipoprotein cholesterol levels (9.4 percent and 16.5 percent, respectively) and significant increases in high-density lipoprotein cholesterol levels (18.8 percent and 14.2 percent, respectively); however, neither treatment altered the progression of coronary atherosclerosis. After adjustment for measurements at base line, the mean (+/-SE) minimal coronary-artery diameters at follow-up were 1.87+/-0.02 mm, 1.84+/-0.02 mm, and 1.87+/-0.02 mm in women assigned to estrogen, estrogen plus medroxyprogesterone acetate, and placebo, respectively. The differences between the values for the two active-treatment groups and the value for the placebo group were not significant. Analyses of several secondary angiographic outcomes and subgroups of women produced similar results. The rates of clinical cardiovascular events were also similar among the treatment groups. Neither estrogen alone nor estrogen plus medroxyprogesterone acetate affected the progression of coronary atherosclerosis in women with established disease. These results suggest that such women should not use estrogen replacement with an expectation of cardiovascular benefit.
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            Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen.

            Estrogen is an important vasoprotective molecule that causes the rapid dilation of blood vessels by activating endothelial nitric oxide synthase (eNOS) through an unknown mechanism. In studies of intact ovine endothelial cells, 17beta-estradiol (E2) caused acute (five-minute) activation of eNOS that was unaffected by actinomycin D but was fully inhibited by concomitant acute treatment with specific estrogen receptor (ER) antagonists. Overexpression of the known transcription factor ERalpha led to marked enhancement of the acute response to E2, and this was blocked by ER antagonists, was specific to E2, and required the ERalpha hormone-binding domain. In addition, the acute response of eNOS to E2 was reconstituted in COS-7 cells cotransfected with wild-type ERalpha and eNOS, but not by transfection with eNOS alone. Furthermore, the inhibition of tyrosine kinases or mitogen-activated protein (MAP) kinase kinase prevented the activation of eNOS by E2, and E2 caused rapid ER-dependent activation of MAP kinase. These findings demonstrate that the short-term effects of estrogen central to cardiovascular physiology are mediated by ERalpha functioning in a novel, nongenomic manner to activate eNOS via MAP kinase-dependent mechanisms.
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              Menopause and risk factors for coronary heart disease.

              Postmenopausal women are believed to have a higher risk of coronary artery disease than premenopausal women. In this study, we prospectively determined changes in coronary risk factors that were attributable to natural menopause in 541 healthy, initially premenopausal women 42 to 50 years of age. After approximately 2 1/2 years, 69 women had spontaneously stopped menstruating for at least 12 months, and 32 women had stopped natural menstruation and received hormone-replacement therapy for a period of at least 12 months. An equal number of age-matched premenopausal women in the study group served as controls. In women who had a natural menopause and did not receive hormone-replacement therapy, serum levels of high-density lipoprotein (HDL) cholesterol declined as compared with those of premenopausal controls (-0.09 vs. 0.00 mmol per liter; P = 0.01), and levels of low-density lipoprotein (LDL) cholesterol increased (+0.31 vs. +0.14 mmol per liter; P = 0.04). In menopausal women who received hormone-replacement therapy, HDL and LDL cholesterol levels did not change, but the levels of triglycerides (+0.42 vs. -0.04 mmol per liter; P less than 0.001), apolipoprotein A-I (+0.18 vs. +0.03 g per liter; P less than 0.01), and apolipoprotein A-II (+0.05 vs. -0.03 g per liter; P less than 0.05) increased as compared with premenopausal controls. Natural menopause did not affect blood pressure, plasma glucose or insulin levels, body weight, the total number of kilojoules consumed in the diet, or the total number of kilojoules expended in physical activity. These results suggest that a natural menopause has an unfavorable effect on lipid metabolism, which may contribute to an increase in the risk of coronary disease. Hormone-replacement therapy may prevent some of these changes.
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                Author and article information

                Journal
                CED
                Cerebrovasc Dis
                10.1159/issn.1015-9770
                Cerebrovascular Diseases
                S. Karger AG
                978-3-8055-8122-6
                978-3-318-01350-4
                1015-9770
                1421-9786
                2006
                May 2006
                04 May 2006
                : 21
                : Suppl 2
                : 48-53
                Affiliations
                aServicio de Neurología, Hospital Universitario Ramón y Cajal, and bUnidad de Ictus, Servicio de Neurología, Hospital Clínico Universitario San Carlos, Madrid, Spain
                Article
                91703 Cerebrovasc Dis 2006;21:48–53
                10.1159/000091703
                16651814
                © 2006 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.

                Page count
                References: 74, Pages: 6
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