Progesterone receptors: a key for neuroprotection in experimental stroke

Autores
Liu, Ailing; Margaill, Isabelle; Zhang, Shaodong; Labombarda, Maria Florencia; Coqueran, Bérard; Delespierre, Brigitte; Liere, Philippe; Marchand Leroux, Catherine; O’Malley, Bert W.; Lydon, John P.; de Nicola, Alejandro Federico; Sitruk Ware, Regine; Mattern, Claudia; Plotkine, Michel; Schumacher, Michael; Guennoun, Rachida
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Progesterone receptors (PR) are expressed throughout the brain. However, their functional significance remains understudied. Here we report a novel role of PR as crucial mediators of neuroprotection using a model of transient middle cerebral artery occlusion and PR knockout mice. Six hours after ischemia, we observed a rapid increase in progesterone and 5-dihydroprogesterone, the endogenous PR ligands, a process that may be a part of the natural neuroprotective mechanisms. PR deficiency, and even haploinsufficiency, increases the susceptibility of the brain to stroke damage. Within a time window of 24 h, PR-dependent signaling of endogenous brain progesterone limits the extent of tissue damage and the impairment of motor functions. Longer-term improvement requires additional treatment with exogenous progesterone and is also PR dependent. The potent and selective PR agonist Nestorone is also effective. In contrast to progesterone, levels of the neurosteroid allopregnanolone, which modulates -aminobutyric acid type A receptors, did not increase after stroke, but its administration protected both wild-type and PR-deficient mice against ischemic damage. These results show that 1) PR are linked to signaling pathways that influence susceptibility to stroke, and 2) PR are direct key targets for both endogenous neuroprotection and for therapeutic strategies after stroke, and they suggest a novel indication for synthetic progestins already validated for contraception. Although allopregnanolone may not be an endogenous neuroprotective agent, its administration protects the brain against ischemicdamageby signaling mechanisms not involving PR. Collectively, our data clarify the relative roles of PR and allopregnanolone in neuroprotection after stroke.
Fil: Liu, Ailing. Institut National de la Santé et de la Recherche Médicale; Francia. Université Paris Sud; Francia
Fil: Margaill, Isabelle. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Paris V; Francia. University Paris Descartes; Francia
Fil: Zhang, Shaodong. Institut National de la Santé et de la Recherche Médicale; Francia. Université Paris Sud; Francia
Fil: Labombarda, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina
Fil: Coqueran, Bérard. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Paris V; Francia
Fil: Delespierre, Brigitte. Université Paris Sud; Francia. Institut National de la Santé et de la Recherche Médicale; Francia
Fil: Liere, Philippe. Université Paris Sud; Francia. Institut National de la Santé et de la Recherche Médicale; Francia
Fil: Marchand Leroux, Catherine. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Paris V; Francia
Fil: O’Malley, Bert W.. Baylor College of Medicine;
Fil: Lydon, John P.. Baylor College of Medicine;
Fil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Sitruk Ware, Regine. The Rockefeller University; Estados Unidos
Fil: Mattern, Claudia. MetP Pharma AG; Suiza
Fil: Plotkine, Michel. Universite de Paris V; Francia
Fil: Schumacher, Michael. Institut National de la Santé et de la Recherche Médicale; Francia. Université Paris Sud; Francia
Fil: Guennoun, Rachida. Université Paris Sud; Francia. Institut National de la Santé et de la Recherche Médicale; Francia
Materia
PROGESTERONE
STROKE
NEUROPROTECTION
THERAPEUTIC USES
SIGNAL TRANSDUCTION
PREGNANOLONE
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:11336/148702
Acceder
id CONICETDig_3a993f21262eb456a5ed050f39810636
oai_identifier_str oai:ri.conicet.gov.ar:11336/148702
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Progesterone receptors: a key for neuroprotection in experimental strokeLiu, AilingMargaill, IsabelleZhang, ShaodongLabombarda, Maria FlorenciaCoqueran, BérardDelespierre, BrigitteLiere, PhilippeMarchand Leroux, CatherineO’Malley, Bert W.Lydon, John P.de Nicola, Alejandro FedericoSitruk Ware, RegineMattern, ClaudiaPlotkine, MichelSchumacher, MichaelGuennoun, RachidaPROGESTERONESTROKENEUROPROTECTIONTHERAPEUTIC USESSIGNAL TRANSDUCTIONPREGNANOLONEhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Progesterone receptors (PR) are expressed throughout the brain. However, their functional significance remains understudied. Here we report a novel role of PR as crucial mediators of neuroprotection using a model of transient middle cerebral artery occlusion and PR knockout mice. Six hours after ischemia, we observed a rapid increase in progesterone and 5-dihydroprogesterone, the endogenous PR ligands, a process that may be a part of the natural neuroprotective mechanisms. PR deficiency, and even haploinsufficiency, increases the susceptibility of the brain to stroke damage. Within a time window of 24 h, PR-dependent signaling of endogenous brain progesterone limits the extent of tissue damage and the impairment of motor functions. Longer-term improvement requires additional treatment with exogenous progesterone and is also PR dependent. The potent and selective PR agonist Nestorone is also effective. In contrast to progesterone, levels of the neurosteroid allopregnanolone, which modulates -aminobutyric acid type A receptors, did not increase after stroke, but its administration protected both wild-type and PR-deficient mice against ischemic damage. These results show that 1) PR are linked to signaling pathways that influence susceptibility to stroke, and 2) PR are direct key targets for both endogenous neuroprotection and for therapeutic strategies after stroke, and they suggest a novel indication for synthetic progestins already validated for contraception. Although allopregnanolone may not be an endogenous neuroprotective agent, its administration protects the brain against ischemicdamageby signaling mechanisms not involving PR. Collectively, our data clarify the relative roles of PR and allopregnanolone in neuroprotection after stroke.Fil: Liu, Ailing. Institut National de la Santé et de la Recherche Médicale; Francia. Université Paris Sud; FranciaFil: Margaill, Isabelle. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Paris V; Francia. University Paris Descartes; FranciaFil: Zhang, Shaodong. Institut National de la Santé et de la Recherche Médicale; Francia. Université Paris Sud; FranciaFil: Labombarda, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; ArgentinaFil: Coqueran, Bérard. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Paris V; FranciaFil: Delespierre, Brigitte. Université Paris Sud; Francia. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Liere, Philippe. Université Paris Sud; Francia. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Marchand Leroux, Catherine. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Paris V; FranciaFil: O’Malley, Bert W.. Baylor College of Medicine;Fil: Lydon, John P.. Baylor College of Medicine;Fil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Sitruk Ware, Regine. The Rockefeller University; Estados UnidosFil: Mattern, Claudia. MetP Pharma AG; SuizaFil: Plotkine, Michel. Universite de Paris V; FranciaFil: Schumacher, Michael. Institut National de la Santé et de la Recherche Médicale; Francia. Université Paris Sud; FranciaFil: Guennoun, Rachida. Université Paris Sud; Francia. Institut National de la Santé et de la Recherche Médicale; FranciaEndocrine Society2012-05info: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/11336/148702Liu, Ailing; Margaill, Isabelle; Zhang, Shaodong; Labombarda, Maria Florencia; Coqueran, Bérard; et al.; Progesterone receptors: a key for neuroprotection in experimental stroke; Endocrine Society; Endocrinology; 153; 8; 5-2012; 3747-37570013-72271945-7170CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/endo/article/153/8/3747/2424008info:eu-repo/semantics/altIdentifier/doi/10.1210/en.2012-1138info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979171/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:36:34Zoai:ri.conicet.gov.ar:11336/148702instacron: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:34982025-09-29 09:36:34.34CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Progesterone receptors: a key for neuroprotection in experimental stroke
title Progesterone receptors: a key for neuroprotection in experimental stroke
spellingShingle Progesterone receptors: a key for neuroprotection in experimental stroke
Liu, Ailing
PROGESTERONE
STROKE
NEUROPROTECTION
THERAPEUTIC USES
SIGNAL TRANSDUCTION
PREGNANOLONE
title_short Progesterone receptors: a key for neuroprotection in experimental stroke
title_full Progesterone receptors: a key for neuroprotection in experimental stroke
title_fullStr Progesterone receptors: a key for neuroprotection in experimental stroke
title_full_unstemmed Progesterone receptors: a key for neuroprotection in experimental stroke
title_sort Progesterone receptors: a key for neuroprotection in experimental stroke
dc.creator.none.fl_str_mv Liu, Ailing
Margaill, Isabelle
Zhang, Shaodong
Labombarda, Maria Florencia
Coqueran, Bérard
Delespierre, Brigitte
Liere, Philippe
Marchand Leroux, Catherine
O’Malley, Bert W.
Lydon, John P.
de Nicola, Alejandro Federico
Sitruk Ware, Regine
Mattern, Claudia
Plotkine, Michel
Schumacher, Michael
Guennoun, Rachida
author Liu, Ailing
author_facet Liu, Ailing
Margaill, Isabelle
Zhang, Shaodong
Labombarda, Maria Florencia
Coqueran, Bérard
Delespierre, Brigitte
Liere, Philippe
Marchand Leroux, Catherine
O’Malley, Bert W.
Lydon, John P.
de Nicola, Alejandro Federico
Sitruk Ware, Regine
Mattern, Claudia
Plotkine, Michel
Schumacher, Michael
Guennoun, Rachida
author_role author
author2 Margaill, Isabelle
Zhang, Shaodong
Labombarda, Maria Florencia
Coqueran, Bérard
Delespierre, Brigitte
Liere, Philippe
Marchand Leroux, Catherine
O’Malley, Bert W.
Lydon, John P.
de Nicola, Alejandro Federico
Sitruk Ware, Regine
Mattern, Claudia
Plotkine, Michel
Schumacher, Michael
Guennoun, Rachida
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv PROGESTERONE
STROKE
NEUROPROTECTION
THERAPEUTIC USES
SIGNAL TRANSDUCTION
PREGNANOLONE
topic PROGESTERONE
STROKE
NEUROPROTECTION
THERAPEUTIC USES
SIGNAL TRANSDUCTION
PREGNANOLONE
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Progesterone receptors (PR) are expressed throughout the brain. However, their functional significance remains understudied. Here we report a novel role of PR as crucial mediators of neuroprotection using a model of transient middle cerebral artery occlusion and PR knockout mice. Six hours after ischemia, we observed a rapid increase in progesterone and 5-dihydroprogesterone, the endogenous PR ligands, a process that may be a part of the natural neuroprotective mechanisms. PR deficiency, and even haploinsufficiency, increases the susceptibility of the brain to stroke damage. Within a time window of 24 h, PR-dependent signaling of endogenous brain progesterone limits the extent of tissue damage and the impairment of motor functions. Longer-term improvement requires additional treatment with exogenous progesterone and is also PR dependent. The potent and selective PR agonist Nestorone is also effective. In contrast to progesterone, levels of the neurosteroid allopregnanolone, which modulates -aminobutyric acid type A receptors, did not increase after stroke, but its administration protected both wild-type and PR-deficient mice against ischemic damage. These results show that 1) PR are linked to signaling pathways that influence susceptibility to stroke, and 2) PR are direct key targets for both endogenous neuroprotection and for therapeutic strategies after stroke, and they suggest a novel indication for synthetic progestins already validated for contraception. Although allopregnanolone may not be an endogenous neuroprotective agent, its administration protects the brain against ischemicdamageby signaling mechanisms not involving PR. Collectively, our data clarify the relative roles of PR and allopregnanolone in neuroprotection after stroke.
Fil: Liu, Ailing. Institut National de la Santé et de la Recherche Médicale; Francia. Université Paris Sud; Francia
Fil: Margaill, Isabelle. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Paris V; Francia. University Paris Descartes; Francia
Fil: Zhang, Shaodong. Institut National de la Santé et de la Recherche Médicale; Francia. Université Paris Sud; Francia
Fil: Labombarda, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina
Fil: Coqueran, Bérard. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Paris V; Francia
Fil: Delespierre, Brigitte. Université Paris Sud; Francia. Institut National de la Santé et de la Recherche Médicale; Francia
Fil: Liere, Philippe. Université Paris Sud; Francia. Institut National de la Santé et de la Recherche Médicale; Francia
Fil: Marchand Leroux, Catherine. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Paris V; Francia
Fil: O’Malley, Bert W.. Baylor College of Medicine;
Fil: Lydon, John P.. Baylor College of Medicine;
Fil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Sitruk Ware, Regine. The Rockefeller University; Estados Unidos
Fil: Mattern, Claudia. MetP Pharma AG; Suiza
Fil: Plotkine, Michel. Universite de Paris V; Francia
Fil: Schumacher, Michael. Institut National de la Santé et de la Recherche Médicale; Francia. Université Paris Sud; Francia
Fil: Guennoun, Rachida. Université Paris Sud; Francia. Institut National de la Santé et de la Recherche Médicale; Francia
description Progesterone receptors (PR) are expressed throughout the brain. However, their functional significance remains understudied. Here we report a novel role of PR as crucial mediators of neuroprotection using a model of transient middle cerebral artery occlusion and PR knockout mice. Six hours after ischemia, we observed a rapid increase in progesterone and 5-dihydroprogesterone, the endogenous PR ligands, a process that may be a part of the natural neuroprotective mechanisms. PR deficiency, and even haploinsufficiency, increases the susceptibility of the brain to stroke damage. Within a time window of 24 h, PR-dependent signaling of endogenous brain progesterone limits the extent of tissue damage and the impairment of motor functions. Longer-term improvement requires additional treatment with exogenous progesterone and is also PR dependent. The potent and selective PR agonist Nestorone is also effective. In contrast to progesterone, levels of the neurosteroid allopregnanolone, which modulates -aminobutyric acid type A receptors, did not increase after stroke, but its administration protected both wild-type and PR-deficient mice against ischemic damage. These results show that 1) PR are linked to signaling pathways that influence susceptibility to stroke, and 2) PR are direct key targets for both endogenous neuroprotection and for therapeutic strategies after stroke, and they suggest a novel indication for synthetic progestins already validated for contraception. Although allopregnanolone may not be an endogenous neuroprotective agent, its administration protects the brain against ischemicdamageby signaling mechanisms not involving PR. Collectively, our data clarify the relative roles of PR and allopregnanolone in neuroprotection after stroke.
publishDate 2012
dc.date.none.fl_str_mv 2012-05
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/11336/148702
Liu, Ailing; Margaill, Isabelle; Zhang, Shaodong; Labombarda, Maria Florencia; Coqueran, Bérard; et al.; Progesterone receptors: a key for neuroprotection in experimental stroke; Endocrine Society; Endocrinology; 153; 8; 5-2012; 3747-3757
0013-7227
1945-7170
CONICET Digital
CONICET
url http://hdl.handle.net/11336/148702
identifier_str_mv Liu, Ailing; Margaill, Isabelle; Zhang, Shaodong; Labombarda, Maria Florencia; Coqueran, Bérard; et al.; Progesterone receptors: a key for neuroprotection in experimental stroke; Endocrine Society; Endocrinology; 153; 8; 5-2012; 3747-3757
0013-7227
1945-7170
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/endo/article/153/8/3747/2424008
info:eu-repo/semantics/altIdentifier/doi/10.1210/en.2012-1138
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979171/
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 Endocrine Society
publisher.none.fl_str_mv Endocrine Society
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 13.070432

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