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Sephin1 Protects Neurons against Excitotoxicity Independently of the Integrated Stress Response

Sephin1 is a derivative of guanabenz that inhibits the dephosphorylation of the eukaryotic initiation factor 2 alpha (eIF2α) and therefore may enhance the integrated stress response (ISR), an adaptive mechanism against different cellular stresses, such as accumulation of misfolded proteins. Unlike g...

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Autores principales: Ruiz, Asier, Zuazo, Jone, Ortiz-Sanz, Carolina, Luchena, Celia, Matute, Carlos, Alberdi, Elena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504470/
https://www.ncbi.nlm.nih.gov/pubmed/32846985
http://dx.doi.org/10.3390/ijms21176088
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author Ruiz, Asier
Zuazo, Jone
Ortiz-Sanz, Carolina
Luchena, Celia
Matute, Carlos
Alberdi, Elena
author_facet Ruiz, Asier
Zuazo, Jone
Ortiz-Sanz, Carolina
Luchena, Celia
Matute, Carlos
Alberdi, Elena
author_sort Ruiz, Asier
collection PubMed
description Sephin1 is a derivative of guanabenz that inhibits the dephosphorylation of the eukaryotic initiation factor 2 alpha (eIF2α) and therefore may enhance the integrated stress response (ISR), an adaptive mechanism against different cellular stresses, such as accumulation of misfolded proteins. Unlike guanabenz, Sephin1 provides neuroprotection without adverse effects on the α2-adrenergic system and therefore it is considered a promising pharmacological therapeutic tool. Here, we have studied the effects of Sephin1 on N-methyl-D-aspartic acid (NMDA) receptor signaling which may modulate the ISR and contribute to excitotoxic neuronal loss in several neurodegenerative conditions. Time-course analysis of peIF2α levels after NMDA receptor overactivation showed a delayed dephosphorylation that occurred in the absence of activating transcription factor 4 (ATF4) and therefore independently of the ISR, in contrast to that observed during endoplasmic reticulum (ER) stress induced by tunicamycin and thapsigargin. Similar to guanabenz, Sephin1 completely blocked NMDA-induced neuronal death and was ineffective against AMPA-induced excitotoxicity, whereas it did not protect from experimental ER stress. Interestingly, both guanabenz and Sephin1 partially but significantly reduced NMDA-induced cytosolic Ca(2+) increase, leading to a complete inhibition of subsequent calpain activation. We conclude that Sephin1 and guanabenz share common strong anti-excitotoxic properties with therapeutic potential unrelated to the ISR.
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spelling pubmed-75044702020-09-24 Sephin1 Protects Neurons against Excitotoxicity Independently of the Integrated Stress Response Ruiz, Asier Zuazo, Jone Ortiz-Sanz, Carolina Luchena, Celia Matute, Carlos Alberdi, Elena Int J Mol Sci Article Sephin1 is a derivative of guanabenz that inhibits the dephosphorylation of the eukaryotic initiation factor 2 alpha (eIF2α) and therefore may enhance the integrated stress response (ISR), an adaptive mechanism against different cellular stresses, such as accumulation of misfolded proteins. Unlike guanabenz, Sephin1 provides neuroprotection without adverse effects on the α2-adrenergic system and therefore it is considered a promising pharmacological therapeutic tool. Here, we have studied the effects of Sephin1 on N-methyl-D-aspartic acid (NMDA) receptor signaling which may modulate the ISR and contribute to excitotoxic neuronal loss in several neurodegenerative conditions. Time-course analysis of peIF2α levels after NMDA receptor overactivation showed a delayed dephosphorylation that occurred in the absence of activating transcription factor 4 (ATF4) and therefore independently of the ISR, in contrast to that observed during endoplasmic reticulum (ER) stress induced by tunicamycin and thapsigargin. Similar to guanabenz, Sephin1 completely blocked NMDA-induced neuronal death and was ineffective against AMPA-induced excitotoxicity, whereas it did not protect from experimental ER stress. Interestingly, both guanabenz and Sephin1 partially but significantly reduced NMDA-induced cytosolic Ca(2+) increase, leading to a complete inhibition of subsequent calpain activation. We conclude that Sephin1 and guanabenz share common strong anti-excitotoxic properties with therapeutic potential unrelated to the ISR. MDPI 2020-08-24 /pmc/articles/PMC7504470/ /pubmed/32846985 http://dx.doi.org/10.3390/ijms21176088 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ruiz, Asier
Zuazo, Jone
Ortiz-Sanz, Carolina
Luchena, Celia
Matute, Carlos
Alberdi, Elena
Sephin1 Protects Neurons against Excitotoxicity Independently of the Integrated Stress Response
title Sephin1 Protects Neurons against Excitotoxicity Independently of the Integrated Stress Response
title_full Sephin1 Protects Neurons against Excitotoxicity Independently of the Integrated Stress Response
title_fullStr Sephin1 Protects Neurons against Excitotoxicity Independently of the Integrated Stress Response
title_full_unstemmed Sephin1 Protects Neurons against Excitotoxicity Independently of the Integrated Stress Response
title_short Sephin1 Protects Neurons against Excitotoxicity Independently of the Integrated Stress Response
title_sort sephin1 protects neurons against excitotoxicity independently of the integrated stress response
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504470/
https://www.ncbi.nlm.nih.gov/pubmed/32846985
http://dx.doi.org/10.3390/ijms21176088
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