In Vitro Modulation of Autophagy by New Antioxidant Nitrones as a Potential Therapeutic Approach for the Treatment of Ischemic Stroke

Stroke is a leading cause of death worldwide, yet current therapeutic strategies remain limited. Among the neuropathological events underlying this disease are multiple cell death signaling cascades, including autophagy. Recent interest has focused on developing agents that target molecules involved...

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Autores: Izquierdo-Bermejo, Sara, Chamorro, Beatriz, Martín-de-Saavedra, María Dolores, Lobete, Miguel, López-Muñoz, Francisco, Marco-Contelles, José, Oset-Gasque, María Jesús
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/371240
Acceso en línea:http://hdl.handle.net/10261/371240
Access Level:acceso abierto
Palabra clave:Autophagy
Cerebral ischemia
Hypoxia
Neuroprotection
Nitrones
Stroke
Therapeutic agents
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spelling In Vitro Modulation of Autophagy by New Antioxidant Nitrones as a Potential Therapeutic Approach for the Treatment of Ischemic StrokeIzquierdo-Bermejo, SaraChamorro, BeatrizMartín-de-Saavedra, María DoloresLobete, MiguelLópez-Muñoz, FranciscoMarco-Contelles, JoséOset-Gasque, María JesúsAutophagyCerebral ischemiaHypoxiaNeuroprotectionNitronesStrokeTherapeutic agentsStroke is a leading cause of death worldwide, yet current therapeutic strategies remain limited. Among the neuropathological events underlying this disease are multiple cell death signaling cascades, including autophagy. Recent interest has focused on developing agents that target molecules involved in autophagy to modulate this process under pathological conditions. This study aimed to analyze the role of autophagy in cell death induced by an in vitro ischemia–reperfusion (IR) model and to determine whether nitrones, known for their neuroprotective and antioxidant effects, could modulate this process. We focused on key proteins involved in different phases of autophagy: HIF-1α, BNIP3, and BECN1 for induction and nucleation, LC3 for elongation, and p62 for degradation. Our findings confirmed that the IR model promotes autophagy, initially via HIF-1α activation. Additionally, the neuroprotective effect of three of the selected synthetic nitrones (quinolylnitrones QN6 and QN23, and homo-bis-nitrone HBN6) partially derives from their antiautophagic properties, demonstrated by a downregulation of the expression of molecular markers involved in various phases of autophagy. In contrast, the neuroprotective power of cholesteronitrone ChN2 seems to derive from its promoting effects on the initial phases of autophagy, which could potentially help inhibit other forms of cell death. These results underscore the importance of autophagy modulation in neuroprotection, highlighting the potential of inhibiting prodeath autophagy and promoting prosurvival autophagy as promising therapeutic approaches in treating ischemic stroke clinically.This research was supported by grants from the Spanish Ministry of Economy and Com- petitiveness (SAF2015-65586-R) to J.M-C., from Camilo José Cela University (UCJC) (Grants “CHON- ICEN” and “NENS”) to M.J.O.-G. and J.M-C., and from the Spanish Research Agency to M.D.M.S, (PID2021-122723OA100).Peer reviewedMultidisciplinary Digital Publishing InstituteMinisterio de Economía y Competitividad (España)Universidad Camilo José CelaAgencia Estatal de Investigación (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/371240reponame: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//SAF2015-65586-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-122723OA-I00https://doi.org/10.3390/antiox13080946Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3712402026-05-22T06:33:51Z
dc.title.none.fl_str_mv In Vitro Modulation of Autophagy by New Antioxidant Nitrones as a Potential Therapeutic Approach for the Treatment of Ischemic Stroke
title In Vitro Modulation of Autophagy by New Antioxidant Nitrones as a Potential Therapeutic Approach for the Treatment of Ischemic Stroke
spellingShingle In Vitro Modulation of Autophagy by New Antioxidant Nitrones as a Potential Therapeutic Approach for the Treatment of Ischemic Stroke
Izquierdo-Bermejo, Sara
Autophagy
Cerebral ischemia
Hypoxia
Neuroprotection
Nitrones
Stroke
Therapeutic agents
title_short In Vitro Modulation of Autophagy by New Antioxidant Nitrones as a Potential Therapeutic Approach for the Treatment of Ischemic Stroke
title_full In Vitro Modulation of Autophagy by New Antioxidant Nitrones as a Potential Therapeutic Approach for the Treatment of Ischemic Stroke
title_fullStr In Vitro Modulation of Autophagy by New Antioxidant Nitrones as a Potential Therapeutic Approach for the Treatment of Ischemic Stroke
title_full_unstemmed In Vitro Modulation of Autophagy by New Antioxidant Nitrones as a Potential Therapeutic Approach for the Treatment of Ischemic Stroke
title_sort In Vitro Modulation of Autophagy by New Antioxidant Nitrones as a Potential Therapeutic Approach for the Treatment of Ischemic Stroke
dc.creator.none.fl_str_mv Izquierdo-Bermejo, Sara
Chamorro, Beatriz
Martín-de-Saavedra, María Dolores
Lobete, Miguel
López-Muñoz, Francisco
Marco-Contelles, José
Oset-Gasque, María Jesús
author Izquierdo-Bermejo, Sara
author_facet Izquierdo-Bermejo, Sara
Chamorro, Beatriz
Martín-de-Saavedra, María Dolores
Lobete, Miguel
López-Muñoz, Francisco
Marco-Contelles, José
Oset-Gasque, María Jesús
author_role author
author2 Chamorro, Beatriz
Martín-de-Saavedra, María Dolores
Lobete, Miguel
López-Muñoz, Francisco
Marco-Contelles, José
Oset-Gasque, María Jesús
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Universidad Camilo José Cela
Agencia Estatal de Investigación (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Autophagy
Cerebral ischemia
Hypoxia
Neuroprotection
Nitrones
Stroke
Therapeutic agents
topic Autophagy
Cerebral ischemia
Hypoxia
Neuroprotection
Nitrones
Stroke
Therapeutic agents
description Stroke is a leading cause of death worldwide, yet current therapeutic strategies remain limited. Among the neuropathological events underlying this disease are multiple cell death signaling cascades, including autophagy. Recent interest has focused on developing agents that target molecules involved in autophagy to modulate this process under pathological conditions. This study aimed to analyze the role of autophagy in cell death induced by an in vitro ischemia–reperfusion (IR) model and to determine whether nitrones, known for their neuroprotective and antioxidant effects, could modulate this process. We focused on key proteins involved in different phases of autophagy: HIF-1α, BNIP3, and BECN1 for induction and nucleation, LC3 for elongation, and p62 for degradation. Our findings confirmed that the IR model promotes autophagy, initially via HIF-1α activation. Additionally, the neuroprotective effect of three of the selected synthetic nitrones (quinolylnitrones QN6 and QN23, and homo-bis-nitrone HBN6) partially derives from their antiautophagic properties, demonstrated by a downregulation of the expression of molecular markers involved in various phases of autophagy. In contrast, the neuroprotective power of cholesteronitrone ChN2 seems to derive from its promoting effects on the initial phases of autophagy, which could potentially help inhibit other forms of cell death. These results underscore the importance of autophagy modulation in neuroprotection, highlighting the potential of inhibiting prodeath autophagy and promoting prosurvival autophagy as promising therapeutic approaches in treating ischemic stroke clinically.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024
2024
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/10261/371240
url http://hdl.handle.net/10261/371240
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//SAF2015-65586-R
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-122723OA-I00
https://doi.org/10.3390/antiox13080946
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
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
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repository.mail.fl_str_mv
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