γ-Glutamylcysteine Alleviates Ischemic Stroke-Induced Neuronal Apoptosis by Inhibiting ROS-Mediated Endoplasmic Reticulum Stress

Ischemic stroke is a severe and acute neurological disorder with limited therapeutic strategies currently available. Oxidative stress is one of the critical pathological factors in ischemia/reperfusion injury, and high levels of reactive oxygen species (ROS) may drive neuronal apoptosis. Rescuing ne...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Hui-qin, Xia, Sheng-nan, Xu, Si-yi, Liu, Pin-yi, Gu, Yue, Bao, Xin-yu, Xu, Yun, Cao, Xiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610689/
https://www.ncbi.nlm.nih.gov/pubmed/34824669
http://dx.doi.org/10.1155/2021/2961079
_version_ 1784603143121666048
author Li, Hui-qin
Xia, Sheng-nan
Xu, Si-yi
Liu, Pin-yi
Gu, Yue
Bao, Xin-yu
Xu, Yun
Cao, Xiang
author_facet Li, Hui-qin
Xia, Sheng-nan
Xu, Si-yi
Liu, Pin-yi
Gu, Yue
Bao, Xin-yu
Xu, Yun
Cao, Xiang
author_sort Li, Hui-qin
collection PubMed
description Ischemic stroke is a severe and acute neurological disorder with limited therapeutic strategies currently available. Oxidative stress is one of the critical pathological factors in ischemia/reperfusion injury, and high levels of reactive oxygen species (ROS) may drive neuronal apoptosis. Rescuing neurons in the penumbra is a potential way to recover from ischemic stroke. Endogenous levels of the potent ROS quencher glutathione (GSH) decrease significantly after cerebral ischemia. Here, we aimed to investigate the neuroprotective effects of γ-glutamylcysteine (γ-GC), an immediate precursor of GSH, on neuronal apoptosis and brain injury during ischemic stroke. Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) were used to mimic cerebral ischemia in mice, neuronal cell lines, and primary neurons. Our data indicated that exogenous γ-GC treatment mitigated oxidative stress, as indicated by upregulated GSH and decreased ROS levels. In addition, γ-GC attenuated ischemia/reperfusion-induced neuronal apoptosis and brain injury in vivo and in vitro. Furthermore, transcriptomics approaches and subsequent validation studies revealed that γ-GC attenuated penumbra neuronal apoptosis by inhibiting the activation of protein kinase R-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1α (IRE1α) in the endoplasmic reticulum (ER) stress signaling pathway in OGD/R-treated cells and ischemic brain tissues. To the best of our knowledge, this study is the first to report that γ-GC attenuates ischemia-induced neuronal apoptosis by suppressing ROS-mediated ER stress. γ-GC may be a promising therapeutic agent for ischemic stroke.
format Online
Article
Text
id pubmed-8610689
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Hindawi
record_format MEDLINE/PubMed
spelling pubmed-86106892021-11-24 γ-Glutamylcysteine Alleviates Ischemic Stroke-Induced Neuronal Apoptosis by Inhibiting ROS-Mediated Endoplasmic Reticulum Stress Li, Hui-qin Xia, Sheng-nan Xu, Si-yi Liu, Pin-yi Gu, Yue Bao, Xin-yu Xu, Yun Cao, Xiang Oxid Med Cell Longev Research Article Ischemic stroke is a severe and acute neurological disorder with limited therapeutic strategies currently available. Oxidative stress is one of the critical pathological factors in ischemia/reperfusion injury, and high levels of reactive oxygen species (ROS) may drive neuronal apoptosis. Rescuing neurons in the penumbra is a potential way to recover from ischemic stroke. Endogenous levels of the potent ROS quencher glutathione (GSH) decrease significantly after cerebral ischemia. Here, we aimed to investigate the neuroprotective effects of γ-glutamylcysteine (γ-GC), an immediate precursor of GSH, on neuronal apoptosis and brain injury during ischemic stroke. Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) were used to mimic cerebral ischemia in mice, neuronal cell lines, and primary neurons. Our data indicated that exogenous γ-GC treatment mitigated oxidative stress, as indicated by upregulated GSH and decreased ROS levels. In addition, γ-GC attenuated ischemia/reperfusion-induced neuronal apoptosis and brain injury in vivo and in vitro. Furthermore, transcriptomics approaches and subsequent validation studies revealed that γ-GC attenuated penumbra neuronal apoptosis by inhibiting the activation of protein kinase R-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1α (IRE1α) in the endoplasmic reticulum (ER) stress signaling pathway in OGD/R-treated cells and ischemic brain tissues. To the best of our knowledge, this study is the first to report that γ-GC attenuates ischemia-induced neuronal apoptosis by suppressing ROS-mediated ER stress. γ-GC may be a promising therapeutic agent for ischemic stroke. Hindawi 2021-11-16 /pmc/articles/PMC8610689/ /pubmed/34824669 http://dx.doi.org/10.1155/2021/2961079 Text en Copyright © 2021 Hui-qin Li et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Li, Hui-qin
Xia, Sheng-nan
Xu, Si-yi
Liu, Pin-yi
Gu, Yue
Bao, Xin-yu
Xu, Yun
Cao, Xiang
γ-Glutamylcysteine Alleviates Ischemic Stroke-Induced Neuronal Apoptosis by Inhibiting ROS-Mediated Endoplasmic Reticulum Stress
title γ-Glutamylcysteine Alleviates Ischemic Stroke-Induced Neuronal Apoptosis by Inhibiting ROS-Mediated Endoplasmic Reticulum Stress
title_full γ-Glutamylcysteine Alleviates Ischemic Stroke-Induced Neuronal Apoptosis by Inhibiting ROS-Mediated Endoplasmic Reticulum Stress
title_fullStr γ-Glutamylcysteine Alleviates Ischemic Stroke-Induced Neuronal Apoptosis by Inhibiting ROS-Mediated Endoplasmic Reticulum Stress
title_full_unstemmed γ-Glutamylcysteine Alleviates Ischemic Stroke-Induced Neuronal Apoptosis by Inhibiting ROS-Mediated Endoplasmic Reticulum Stress
title_short γ-Glutamylcysteine Alleviates Ischemic Stroke-Induced Neuronal Apoptosis by Inhibiting ROS-Mediated Endoplasmic Reticulum Stress
title_sort γ-glutamylcysteine alleviates ischemic stroke-induced neuronal apoptosis by inhibiting ros-mediated endoplasmic reticulum stress
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610689/
https://www.ncbi.nlm.nih.gov/pubmed/34824669
http://dx.doi.org/10.1155/2021/2961079
work_keys_str_mv AT lihuiqin gglutamylcysteinealleviatesischemicstrokeinducedneuronalapoptosisbyinhibitingrosmediatedendoplasmicreticulumstress
AT xiashengnan gglutamylcysteinealleviatesischemicstrokeinducedneuronalapoptosisbyinhibitingrosmediatedendoplasmicreticulumstress
AT xusiyi gglutamylcysteinealleviatesischemicstrokeinducedneuronalapoptosisbyinhibitingrosmediatedendoplasmicreticulumstress
AT liupinyi gglutamylcysteinealleviatesischemicstrokeinducedneuronalapoptosisbyinhibitingrosmediatedendoplasmicreticulumstress
AT guyue gglutamylcysteinealleviatesischemicstrokeinducedneuronalapoptosisbyinhibitingrosmediatedendoplasmicreticulumstress
AT baoxinyu gglutamylcysteinealleviatesischemicstrokeinducedneuronalapoptosisbyinhibitingrosmediatedendoplasmicreticulumstress
AT xuyun gglutamylcysteinealleviatesischemicstrokeinducedneuronalapoptosisbyinhibitingrosmediatedendoplasmicreticulumstress
AT caoxiang gglutamylcysteinealleviatesischemicstrokeinducedneuronalapoptosisbyinhibitingrosmediatedendoplasmicreticulumstress