The MDM2-p53 pathway is involved in preconditioning-induced neuronal tolerance to ischemia

Abstract Brain preconditioning (PC) refers to a state of transient tolerance against a lethal insult that can be evoked by a prior mild event. It is thought that PC may induce different pathways responsible for neuroprotection, which may involve the attenuation of cell damage pathways, including the...

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Autores principales:	Rebeca Vecino, Maria C. Burguete, Teresa Jover-Mengual, Jesus Agulla, Verónica Bobo-Jiménez, Juan B. Salom, Angeles Almeida, Maria Delgado-Esteban
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7d5f510a33134e7a88cb679243ce66fa
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spelling	oai:doaj.org-article:7d5f510a33134e7a88cb679243ce66fa2021-12-02T15:07:44ZThe MDM2-p53 pathway is involved in preconditioning-induced neuronal tolerance to ischemia10.1038/s41598-018-19921-x2045-2322https://doaj.org/article/7d5f510a33134e7a88cb679243ce66fa2018-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-19921-xhttps://doaj.org/toc/2045-2322Abstract Brain preconditioning (PC) refers to a state of transient tolerance against a lethal insult that can be evoked by a prior mild event. It is thought that PC may induce different pathways responsible for neuroprotection, which may involve the attenuation of cell damage pathways, including the apoptotic cell death. In this context, p53 is a stress sensor that accumulates during brain ischemia leading to neuronal death. The murine double minute 2 gene (MDM2), a p53-specific E3 ubiquitin ligase, is the main cellular antagonist of p53, mediating its degradation by the proteasome. Here, we study the role of MDM2-p53 pathway on PC-induced neuroprotection both in cultured neurons (in vitro) and rat brain (in vivo). Our results show that PC increased neuronal MDM2 protein levels, which prevented ischemia-induced p53 stabilization and neuronal death. Indeed, PC attenuated ischemia-induced activation of the p53/PUMA/caspase-3 signaling pathway. Pharmacological inhibition of MDM2-p53 interaction in neurons abrogated PC-induced neuroprotection against ischemia. Finally, the relevance of the MDM2-p53 pathway was confirmed in rat brain using a PC model in vivo. These findings demonstrate the key role of the MDM2-p53 pathway in PC-induced neuroprotection against a subsequent ischemic insult and poses MDM2 as an essential target in ischemic tolerance.Rebeca VecinoMaria C. BurgueteTeresa Jover-MengualJesus AgullaVerónica Bobo-JiménezJuan B. SalomAngeles AlmeidaMaria Delgado-EstebanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-15 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rebeca Vecino Maria C. Burguete Teresa Jover-Mengual Jesus Agulla Verónica Bobo-Jiménez Juan B. Salom Angeles Almeida Maria Delgado-Esteban The MDM2-p53 pathway is involved in preconditioning-induced neuronal tolerance to ischemia
description	Abstract Brain preconditioning (PC) refers to a state of transient tolerance against a lethal insult that can be evoked by a prior mild event. It is thought that PC may induce different pathways responsible for neuroprotection, which may involve the attenuation of cell damage pathways, including the apoptotic cell death. In this context, p53 is a stress sensor that accumulates during brain ischemia leading to neuronal death. The murine double minute 2 gene (MDM2), a p53-specific E3 ubiquitin ligase, is the main cellular antagonist of p53, mediating its degradation by the proteasome. Here, we study the role of MDM2-p53 pathway on PC-induced neuroprotection both in cultured neurons (in vitro) and rat brain (in vivo). Our results show that PC increased neuronal MDM2 protein levels, which prevented ischemia-induced p53 stabilization and neuronal death. Indeed, PC attenuated ischemia-induced activation of the p53/PUMA/caspase-3 signaling pathway. Pharmacological inhibition of MDM2-p53 interaction in neurons abrogated PC-induced neuroprotection against ischemia. Finally, the relevance of the MDM2-p53 pathway was confirmed in rat brain using a PC model in vivo. These findings demonstrate the key role of the MDM2-p53 pathway in PC-induced neuroprotection against a subsequent ischemic insult and poses MDM2 as an essential target in ischemic tolerance.
format	article
author	Rebeca Vecino Maria C. Burguete Teresa Jover-Mengual Jesus Agulla Verónica Bobo-Jiménez Juan B. Salom Angeles Almeida Maria Delgado-Esteban
author_facet	Rebeca Vecino Maria C. Burguete Teresa Jover-Mengual Jesus Agulla Verónica Bobo-Jiménez Juan B. Salom Angeles Almeida Maria Delgado-Esteban
author_sort	Rebeca Vecino
title	The MDM2-p53 pathway is involved in preconditioning-induced neuronal tolerance to ischemia
title_short	The MDM2-p53 pathway is involved in preconditioning-induced neuronal tolerance to ischemia
title_full	The MDM2-p53 pathway is involved in preconditioning-induced neuronal tolerance to ischemia
title_fullStr	The MDM2-p53 pathway is involved in preconditioning-induced neuronal tolerance to ischemia
title_full_unstemmed	The MDM2-p53 pathway is involved in preconditioning-induced neuronal tolerance to ischemia
title_sort	mdm2-p53 pathway is involved in preconditioning-induced neuronal tolerance to ischemia
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/7d5f510a33134e7a88cb679243ce66fa
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The MDM2-p53 pathway is involved in preconditioning-induced neuronal tolerance to ischemia

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