Cerebroprotective Effect of 17β-Estradiol Replacement Therapy in Ovariectomy-Induced Post-Menopausal Rats Subjected to Ischemic Stroke: Role of MAPK/ERK1/2 Pathway and PI3K-Independent Akt Activation
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Published:2023-09-19
Issue:18
Volume:24
Page:14303
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Burguete María C.12, Jover-Mengual Teresa12, Castelló-Ruiz María13ORCID, López-Morales Mikahela A.14ORCID, Centeno José M.12ORCID, Aliena-Valero Alicia14, Alborch Enrique12, Torregrosa Germán14, Salom Juan B.124ORCID
Affiliation:
1. Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Universitat de València, 46100 Burjassot, Spain 2. Departamento de Fisiología, Universitat de València, 46100 Burjassot, Spain 3. Departamento de Biología Celular, Biología Funcional y Antropología Física, Universitat de València, 46100 Burjassot, Spain 4. Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain
Abstract
Despite the overwhelming advances in the understanding of the pathogenesis of stroke, a devastating disease affecting millions of people worldwide, currently there are only a limited number of effective treatments available. Preclinical and clinical studies show that stroke is a sexually dimorphic disorder, affecting males and females differently. Strong experimental evidence indicates that estrogen may play a role in this difference and that exogenous 17β-estradiol (E2) is neuroprotective against stroke in both male and female rodents. However, the molecular mechanisms by which E2 intervenes in ischemia-induced cell death, revealing these sex differences, remain unclear. The present study was aimed to determine, in female rats, the molecular mechanisms of two well-known pro-survival signaling pathways, MAPK/ERK1/2 and PI3K/Akt, that mediate E2 neuroprotection in response to acute ischemic stroke. E2 pretreatment reduced brain damage and attenuated apoptotic cell death in ovariectomized female rats after an ischemic insult. Moreover, E2 decreased phosphorylation of ERK1/2 and prevented ischemia/reperfusion-induced dephosphorylation of both Akt and the pro-apoptotic protein, BAD. However, MAPK/ERK1/2 inhibitor PD98059, but not the PI3K inhibitor LY294002, attenuated E2 neuroprotection. Thus, these results suggested that E2 pretreatment in ovariectomized female rats modulates MAPK/ERK1/2 and activates Akt independently of PI3K to promote cerebroprotection in ischemic stroke. A better understanding of the mechanisms and the influence of E2 in the female sex paves the way for the design of future successful hormone replacement therapies.
Funder
Conselleria de Sanitat Generalitat Valenciana Conselleria de Educación de la Generalitat Valenciana, Spain Universitat de València, Spain Instituto de Salud Carlos III, Spain
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference66 articles.
1. GBD 2019 Stroke Collaborators (2021). Global, regional, and national burden of stroke and its risk factors, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol., 20, 795–820. 2. Elucidating sex differences in response to cerebral ischemia: Immunoregulatory mechanisms and the role of microRNAs;Kaidonis;Prog. Neurobiol.,2019 3. Sex differences in stroke co-morbidities;Branyan;Exp. Neurol.,2020 4. Stroke in women: When gender matters;Thomas;Rev. Neurol.,2021 5. Sex differences in ischaemic stroke: Potential cellular mechanisms;Chauhan;Clin. Sci.,2017
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