Mifepristone, a blocker of glucocorticoid receptors, promotes photoreceptor death

Autores
Cubilla, Marisa Angélica; Bermúdez, Vicente; Marquioni Ramella, Melisa Daniela; Bachor, Tomás Pedro; Suburo, Angela Maria
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
PURPOSE: Glucocorticoids are best known by their protective effect on retinal photoreceptor damage. However, they could also be involved in photoreceptor homeostasis under basal, nonstressful conditions. Therefore, we aimed to study glucocorticoid-induced changes of survival-related molecules in male mice retinas under standard illumination conditions (12 hours light, ≤ 60 lux/12 h dark). METHODS: Male Balb-c mice were injected with dexamethasone (DEX), a selective glucocorticoid receptor α (GRα) agonist, its antagonist mifepristone (MFP), or both drugs (D+M) at noon. A group of mice was subjected to surgical adrenalectomy (AdrX). Retinas were studied by histology, immunohistochemistry, TUNEL procedure, and Western blotting at different periods after pharmacological or surgical intervention (6 hours, 48 hours, or 7 days). RESULTS: The antiapoptotic molecule Bcl-X(L) significantly increased 6 hours after DEX injection. By contrast, this molecule could no longer be found after MFP injection. At the same time, high levels of cleaved caspase-3 (CC-3) and Bax appeared in retinal extracts, and TUNEL(+) nuclei selectively showed in the outer nuclear layer (ONL). After MFP, retinal extracts also contained phosphorylated histone H2AX (p-H2AX), a marker of DNA breakage and repair. Loss of ONL nuclear rows and decrease of rhodopsin levels were evident 7 days after MFP administration. These changes were minimized when DEX was given together with MFP (D+M). In the absence of MFP, DEX increased Bcl-X(L) in every retinal layer, with a marked intensification in photoreceptor inner segments. Numerous TUNEL(+) nuclei rapidly appeared in the ONL after AdrX. CONCLUSIONS: A single dose of MFP induced selective photoreceptor damage in the absence of other environmental stressors. Because damage was prevented by DEX, and was reproduced by AdrX, our findings suggest that glucocorticoids play a critical role in photoreceptor survival.
Fil: Cubilla, Marisa Angélica. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Bermúdez, Vicente. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Marquioni Ramella, Melisa Daniela. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Bachor, Tomás Pedro. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Suburo, Angela Maria. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
RETINA
MIFEPRISTONE
GLUCOCORTICOIDS
APOPTOSIS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/21279
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/21279
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Mifepristone, a blocker of glucocorticoid receptors, promotes photoreceptor deathCubilla, Marisa AngélicaBermúdez, VicenteMarquioni Ramella, Melisa DanielaBachor, Tomás PedroSuburo, Angela MariaRETINAMIFEPRISTONEGLUCOCORTICOIDSAPOPTOSIShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3PURPOSE: Glucocorticoids are best known by their protective effect on retinal photoreceptor damage. However, they could also be involved in photoreceptor homeostasis under basal, nonstressful conditions. Therefore, we aimed to study glucocorticoid-induced changes of survival-related molecules in male mice retinas under standard illumination conditions (12 hours light, ≤ 60 lux/12 h dark). METHODS: Male Balb-c mice were injected with dexamethasone (DEX), a selective glucocorticoid receptor α (GRα) agonist, its antagonist mifepristone (MFP), or both drugs (D+M) at noon. A group of mice was subjected to surgical adrenalectomy (AdrX). Retinas were studied by histology, immunohistochemistry, TUNEL procedure, and Western blotting at different periods after pharmacological or surgical intervention (6 hours, 48 hours, or 7 days). RESULTS: The antiapoptotic molecule Bcl-X(L) significantly increased 6 hours after DEX injection. By contrast, this molecule could no longer be found after MFP injection. At the same time, high levels of cleaved caspase-3 (CC-3) and Bax appeared in retinal extracts, and TUNEL(+) nuclei selectively showed in the outer nuclear layer (ONL). After MFP, retinal extracts also contained phosphorylated histone H2AX (p-H2AX), a marker of DNA breakage and repair. Loss of ONL nuclear rows and decrease of rhodopsin levels were evident 7 days after MFP administration. These changes were minimized when DEX was given together with MFP (D+M). In the absence of MFP, DEX increased Bcl-X(L) in every retinal layer, with a marked intensification in photoreceptor inner segments. Numerous TUNEL(+) nuclei rapidly appeared in the ONL after AdrX. CONCLUSIONS: A single dose of MFP induced selective photoreceptor damage in the absence of other environmental stressors. Because damage was prevented by DEX, and was reproduced by AdrX, our findings suggest that glucocorticoids play a critical role in photoreceptor survival.Fil: Cubilla, Marisa Angélica. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bermúdez, Vicente. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Marquioni Ramella, Melisa Daniela. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bachor, Tomás Pedro. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Suburo, Angela Maria. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaAssociation for Research in Vision and Ophthalmology2013-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/21279Cubilla, Marisa Angélica; Bermúdez, Vicente; Marquioni Ramella, Melisa Daniela; Bachor, Tomás Pedro; Suburo, Angela Maria; Mifepristone, a blocker of glucocorticoid receptors, promotes photoreceptor death; Association for Research in Vision and Ophthalmology; Investigative Ophthalmology & Visual Science; 54; 1; 1-2013; 313-3220146-04041552-5783CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://iovs.arvojournals.org/article.aspx?articleid=2188784#90707692info:eu-repo/semantics/altIdentifier/doi/10.1167/iovs.12-10014info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:46:15Zoai:ri.conicet.gov.ar:11336/21279instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:46:15.41CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Mifepristone, a blocker of glucocorticoid receptors, promotes photoreceptor death
title Mifepristone, a blocker of glucocorticoid receptors, promotes photoreceptor death
spellingShingle Mifepristone, a blocker of glucocorticoid receptors, promotes photoreceptor death
Cubilla, Marisa Angélica
RETINA
MIFEPRISTONE
GLUCOCORTICOIDS
APOPTOSIS
title_short Mifepristone, a blocker of glucocorticoid receptors, promotes photoreceptor death
title_full Mifepristone, a blocker of glucocorticoid receptors, promotes photoreceptor death
title_fullStr Mifepristone, a blocker of glucocorticoid receptors, promotes photoreceptor death
title_full_unstemmed Mifepristone, a blocker of glucocorticoid receptors, promotes photoreceptor death
title_sort Mifepristone, a blocker of glucocorticoid receptors, promotes photoreceptor death
dc.creator.none.fl_str_mv Cubilla, Marisa Angélica
Bermúdez, Vicente
Marquioni Ramella, Melisa Daniela
Bachor, Tomás Pedro
Suburo, Angela Maria
author Cubilla, Marisa Angélica
author_facet Cubilla, Marisa Angélica
Bermúdez, Vicente
Marquioni Ramella, Melisa Daniela
Bachor, Tomás Pedro
Suburo, Angela Maria
author_role author
author2 Bermúdez, Vicente
Marquioni Ramella, Melisa Daniela
Bachor, Tomás Pedro
Suburo, Angela Maria
author2_role author
author
author
author
dc.subject.none.fl_str_mv RETINA
MIFEPRISTONE
GLUCOCORTICOIDS
APOPTOSIS
topic RETINA
MIFEPRISTONE
GLUCOCORTICOIDS
APOPTOSIS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv PURPOSE: Glucocorticoids are best known by their protective effect on retinal photoreceptor damage. However, they could also be involved in photoreceptor homeostasis under basal, nonstressful conditions. Therefore, we aimed to study glucocorticoid-induced changes of survival-related molecules in male mice retinas under standard illumination conditions (12 hours light, ≤ 60 lux/12 h dark). METHODS: Male Balb-c mice were injected with dexamethasone (DEX), a selective glucocorticoid receptor α (GRα) agonist, its antagonist mifepristone (MFP), or both drugs (D+M) at noon. A group of mice was subjected to surgical adrenalectomy (AdrX). Retinas were studied by histology, immunohistochemistry, TUNEL procedure, and Western blotting at different periods after pharmacological or surgical intervention (6 hours, 48 hours, or 7 days). RESULTS: The antiapoptotic molecule Bcl-X(L) significantly increased 6 hours after DEX injection. By contrast, this molecule could no longer be found after MFP injection. At the same time, high levels of cleaved caspase-3 (CC-3) and Bax appeared in retinal extracts, and TUNEL(+) nuclei selectively showed in the outer nuclear layer (ONL). After MFP, retinal extracts also contained phosphorylated histone H2AX (p-H2AX), a marker of DNA breakage and repair. Loss of ONL nuclear rows and decrease of rhodopsin levels were evident 7 days after MFP administration. These changes were minimized when DEX was given together with MFP (D+M). In the absence of MFP, DEX increased Bcl-X(L) in every retinal layer, with a marked intensification in photoreceptor inner segments. Numerous TUNEL(+) nuclei rapidly appeared in the ONL after AdrX. CONCLUSIONS: A single dose of MFP induced selective photoreceptor damage in the absence of other environmental stressors. Because damage was prevented by DEX, and was reproduced by AdrX, our findings suggest that glucocorticoids play a critical role in photoreceptor survival.
Fil: Cubilla, Marisa Angélica. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Bermúdez, Vicente. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Marquioni Ramella, Melisa Daniela. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Bachor, Tomás Pedro. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Suburo, Angela Maria. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description PURPOSE: Glucocorticoids are best known by their protective effect on retinal photoreceptor damage. However, they could also be involved in photoreceptor homeostasis under basal, nonstressful conditions. Therefore, we aimed to study glucocorticoid-induced changes of survival-related molecules in male mice retinas under standard illumination conditions (12 hours light, ≤ 60 lux/12 h dark). METHODS: Male Balb-c mice were injected with dexamethasone (DEX), a selective glucocorticoid receptor α (GRα) agonist, its antagonist mifepristone (MFP), or both drugs (D+M) at noon. A group of mice was subjected to surgical adrenalectomy (AdrX). Retinas were studied by histology, immunohistochemistry, TUNEL procedure, and Western blotting at different periods after pharmacological or surgical intervention (6 hours, 48 hours, or 7 days). RESULTS: The antiapoptotic molecule Bcl-X(L) significantly increased 6 hours after DEX injection. By contrast, this molecule could no longer be found after MFP injection. At the same time, high levels of cleaved caspase-3 (CC-3) and Bax appeared in retinal extracts, and TUNEL(+) nuclei selectively showed in the outer nuclear layer (ONL). After MFP, retinal extracts also contained phosphorylated histone H2AX (p-H2AX), a marker of DNA breakage and repair. Loss of ONL nuclear rows and decrease of rhodopsin levels were evident 7 days after MFP administration. These changes were minimized when DEX was given together with MFP (D+M). In the absence of MFP, DEX increased Bcl-X(L) in every retinal layer, with a marked intensification in photoreceptor inner segments. Numerous TUNEL(+) nuclei rapidly appeared in the ONL after AdrX. CONCLUSIONS: A single dose of MFP induced selective photoreceptor damage in the absence of other environmental stressors. Because damage was prevented by DEX, and was reproduced by AdrX, our findings suggest that glucocorticoids play a critical role in photoreceptor survival.
publishDate 2013
dc.date.none.fl_str_mv 2013-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/21279
Cubilla, Marisa Angélica; Bermúdez, Vicente; Marquioni Ramella, Melisa Daniela; Bachor, Tomás Pedro; Suburo, Angela Maria; Mifepristone, a blocker of glucocorticoid receptors, promotes photoreceptor death; Association for Research in Vision and Ophthalmology; Investigative Ophthalmology & Visual Science; 54; 1; 1-2013; 313-322
0146-0404
1552-5783
CONICET Digital
CONICET
url http://hdl.handle.net/11336/21279
identifier_str_mv Cubilla, Marisa Angélica; Bermúdez, Vicente; Marquioni Ramella, Melisa Daniela; Bachor, Tomás Pedro; Suburo, Angela Maria; Mifepristone, a blocker of glucocorticoid receptors, promotes photoreceptor death; Association for Research in Vision and Ophthalmology; Investigative Ophthalmology & Visual Science; 54; 1; 1-2013; 313-322
0146-0404
1552-5783
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://iovs.arvojournals.org/article.aspx?articleid=2188784#90707692
info:eu-repo/semantics/altIdentifier/doi/10.1167/iovs.12-10014
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Association for Research in Vision and Ophthalmology
publisher.none.fl_str_mv Association for Research in Vision and Ophthalmology
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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