Prevention of excitotoxicity-induced processing of BDNF receptor TrkB-FL leads to stroke neuroprotection

© 2019 The Authors.

Detalles Bibliográficos
Autores: Tejeda, Gonzalo S., Esteban‐Ortega, Gema M., San Antonio, Esther, Gómez Vidaurre, Óscar, Díaz-Guerra, Margarita
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/207321
Acceso en línea:http://hdl.handle.net/10261/207321
Access Level:acceso abierto
Palabra clave:Cell-penetrating peptides
Excitotoxicity
Neuroprotection
Stroke
TrkB
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spelling Prevention of excitotoxicity-induced processing of BDNF receptor TrkB-FL leads to stroke neuroprotectionTejeda, Gonzalo S.Esteban‐Ortega, Gema M.San Antonio, EstherGómez Vidaurre, ÓscarDíaz-Guerra, MargaritaCell-penetrating peptidesExcitotoxicityNeuroprotectionStrokeTrkB© 2019 The Authors.Neuroprotective strategies aimed to pharmacologically treat stroke, a prominent cause of death, disability, and dementia, have remained elusive. A promising approach is restriction of excitotoxic neuronal death in the infarct penumbra through enhancement of survival pathways initiated by brain‐derived neurotrophic factor (BDNF). However, boosting of neurotrophic signaling after ischemia is challenged by downregulation of BDNF high‐affinity receptor, full‐length tropomyosin‐related kinase B (TrkB‐FL), due to calpain‐degradation, and, secondarily, regulated intramembrane proteolysis. Here, we have designed a blood–brain barrier (BBB) permeable peptide containing TrkB‐FL sequences (TFL457) which prevents receptor disappearance from the neuronal surface, early induced after excitotoxicity. In this way, TFL457 interferes TrkB‐FL cleavage by both proteolytic systems and increases neuronal viability via a PLCγ‐dependent mechanism. By preserving downstream CREB and MEF2 promoter activities, TFL457 initiates a feedback mechanism favoring increased levels in excitotoxic neurons of critical prosurvival mRNAs and proteins. This neuroprotective peptide could be highly relevant for stroke therapy since, in a mouse ischemia model, it counteracts TrkB‐FL downregulation in the infarcted brain, efficiently decreases infarct size, and improves neurological outcome.We acknowledge funding from Ministerio de Economía y Competitividad (BFU2013-43808-R and BFU2016-75973-R). The cost of publication has been paid in part by FEDER funds. Contracts were funded associated with projects BFU2013-43808-R (G.S.T and G.M.E-O) and BFU2016-75973-R (G.M.E-O and E.SA).John Wiley & SonsWiley-VCHEMBO PressMinisterio de Economía y Competitividad (España)European CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020192020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/207321reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2013-43808-Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2016-75973-Rhttp://dx.doi.org/10.15252/emmm.201809950Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2073212026-05-22T06:33:51Z
dc.title.none.fl_str_mv Prevention of excitotoxicity-induced processing of BDNF receptor TrkB-FL leads to stroke neuroprotection
title Prevention of excitotoxicity-induced processing of BDNF receptor TrkB-FL leads to stroke neuroprotection
spellingShingle Prevention of excitotoxicity-induced processing of BDNF receptor TrkB-FL leads to stroke neuroprotection
Tejeda, Gonzalo S.
Cell-penetrating peptides
Excitotoxicity
Neuroprotection
Stroke
TrkB
title_short Prevention of excitotoxicity-induced processing of BDNF receptor TrkB-FL leads to stroke neuroprotection
title_full Prevention of excitotoxicity-induced processing of BDNF receptor TrkB-FL leads to stroke neuroprotection
title_fullStr Prevention of excitotoxicity-induced processing of BDNF receptor TrkB-FL leads to stroke neuroprotection
title_full_unstemmed Prevention of excitotoxicity-induced processing of BDNF receptor TrkB-FL leads to stroke neuroprotection
title_sort Prevention of excitotoxicity-induced processing of BDNF receptor TrkB-FL leads to stroke neuroprotection
dc.creator.none.fl_str_mv Tejeda, Gonzalo S.
Esteban‐Ortega, Gema M.
San Antonio, Esther
Gómez Vidaurre, Óscar
Díaz-Guerra, Margarita
author Tejeda, Gonzalo S.
author_facet Tejeda, Gonzalo S.
Esteban‐Ortega, Gema M.
San Antonio, Esther
Gómez Vidaurre, Óscar
Díaz-Guerra, Margarita
author_role author
author2 Esteban‐Ortega, Gema M.
San Antonio, Esther
Gómez Vidaurre, Óscar
Díaz-Guerra, Margarita
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Cell-penetrating peptides
Excitotoxicity
Neuroprotection
Stroke
TrkB
topic Cell-penetrating peptides
Excitotoxicity
Neuroprotection
Stroke
TrkB
description © 2019 The Authors.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/207321
url http://hdl.handle.net/10261/207321
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2013-43808-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2016-75973-R
http://dx.doi.org/10.15252/emmm.201809950
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv John Wiley & Sons
Wiley-VCH
EMBO Press
publisher.none.fl_str_mv John Wiley & Sons
Wiley-VCH
EMBO Press
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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