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Orexin-A exerts neuroprotective effect in experimental intracerebral hemorrhage by suppressing autophagy via OXR1-mediated ERK/mTOR signaling pathway
BACKGROUND: Orexin-A (OXA) is a polypeptide produced in the hypothalamus, which binds to specific receptors and exerts multiple physiological effects. Autophagy plays a vital role in early brain injury (EBI) after intracerebral hemorrhage (ICH). However, the relationship between OXA and autophagy af...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9815810/ https://www.ncbi.nlm.nih.gov/pubmed/36619670 http://dx.doi.org/10.3389/fncel.2022.1045034 |
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author | Zhang, Dexin Cui, Ying Zhao, Manman Zheng, Xuecheng Li, Chunyan Wei, Jingbo Wang, Kaijie Cui, Jianzhong |
author_facet | Zhang, Dexin Cui, Ying Zhao, Manman Zheng, Xuecheng Li, Chunyan Wei, Jingbo Wang, Kaijie Cui, Jianzhong |
author_sort | Zhang, Dexin |
collection | PubMed |
description | BACKGROUND: Orexin-A (OXA) is a polypeptide produced in the hypothalamus, which binds to specific receptors and exerts multiple physiological effects. Autophagy plays a vital role in early brain injury (EBI) after intracerebral hemorrhage (ICH). However, the relationship between OXA and autophagy after ICH has not been confirmed. METHODS: In this study, the protective role of OXA was investigated in a model of hemin-induced injury in PC12 cells and blood-injection ICH model in rats, and its potential molecular mechanism was clarified. Neurobehavioral tests, brain water content, and pathologic morphology were assessed after ICH. Cell survival rate was determined using Cell Counting Kit-8 (CCK-8), while apoptosis was detected using flow cytometry. The autophagy protein LC3 that was originally identified as microtubule-associated protein 1 light 3 was evaluated by immunohistochemistry. The ultrastructural changes of cells following ICH were observed by transmission electron microscopy. Western blotting was performed to determine the expression levels of LC3, p62/SQSTM1 (p62), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK(1/2)), total extracellular signal-regulated kinase 1/2 (t-ERK(1/2)), mammalian target of rapamycin (mTOR), and phosphorylated mammalian target of rapamycin (p-mTOR). RESULTS: OXA treatment significantly improved neurofunctional outcomes, reduced brain edema, and alleviated neuronal apoptosis. OXA administration upregulated p-mTOR and p62, while it downregulated p-ERK(1/2) and LC3; this effect was reversed by the orexin receptor 1 (OXR1) antagonist SB-334867. CONCLUSIONS: This study demonstrates that OXA suppresses autophagy via the OXR1-mediated ERK/mTOR signaling pathway to exert neuroprotective effects, and it might provide a novel therapeutic approach in patients suffering from ICH. |
format | Online Article Text |
id | pubmed-9815810 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-98158102023-01-06 Orexin-A exerts neuroprotective effect in experimental intracerebral hemorrhage by suppressing autophagy via OXR1-mediated ERK/mTOR signaling pathway Zhang, Dexin Cui, Ying Zhao, Manman Zheng, Xuecheng Li, Chunyan Wei, Jingbo Wang, Kaijie Cui, Jianzhong Front Cell Neurosci Neuroscience BACKGROUND: Orexin-A (OXA) is a polypeptide produced in the hypothalamus, which binds to specific receptors and exerts multiple physiological effects. Autophagy plays a vital role in early brain injury (EBI) after intracerebral hemorrhage (ICH). However, the relationship between OXA and autophagy after ICH has not been confirmed. METHODS: In this study, the protective role of OXA was investigated in a model of hemin-induced injury in PC12 cells and blood-injection ICH model in rats, and its potential molecular mechanism was clarified. Neurobehavioral tests, brain water content, and pathologic morphology were assessed after ICH. Cell survival rate was determined using Cell Counting Kit-8 (CCK-8), while apoptosis was detected using flow cytometry. The autophagy protein LC3 that was originally identified as microtubule-associated protein 1 light 3 was evaluated by immunohistochemistry. The ultrastructural changes of cells following ICH were observed by transmission electron microscopy. Western blotting was performed to determine the expression levels of LC3, p62/SQSTM1 (p62), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK(1/2)), total extracellular signal-regulated kinase 1/2 (t-ERK(1/2)), mammalian target of rapamycin (mTOR), and phosphorylated mammalian target of rapamycin (p-mTOR). RESULTS: OXA treatment significantly improved neurofunctional outcomes, reduced brain edema, and alleviated neuronal apoptosis. OXA administration upregulated p-mTOR and p62, while it downregulated p-ERK(1/2) and LC3; this effect was reversed by the orexin receptor 1 (OXR1) antagonist SB-334867. CONCLUSIONS: This study demonstrates that OXA suppresses autophagy via the OXR1-mediated ERK/mTOR signaling pathway to exert neuroprotective effects, and it might provide a novel therapeutic approach in patients suffering from ICH. Frontiers Media S.A. 2022-12-22 /pmc/articles/PMC9815810/ /pubmed/36619670 http://dx.doi.org/10.3389/fncel.2022.1045034 Text en Copyright © 2022 Zhang, Cui, Zhao, Zheng, Li, Wei, Wang and Cui. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Zhang, Dexin Cui, Ying Zhao, Manman Zheng, Xuecheng Li, Chunyan Wei, Jingbo Wang, Kaijie Cui, Jianzhong Orexin-A exerts neuroprotective effect in experimental intracerebral hemorrhage by suppressing autophagy via OXR1-mediated ERK/mTOR signaling pathway |
title | Orexin-A exerts neuroprotective effect in experimental intracerebral hemorrhage by suppressing autophagy via OXR1-mediated ERK/mTOR signaling pathway |
title_full | Orexin-A exerts neuroprotective effect in experimental intracerebral hemorrhage by suppressing autophagy via OXR1-mediated ERK/mTOR signaling pathway |
title_fullStr | Orexin-A exerts neuroprotective effect in experimental intracerebral hemorrhage by suppressing autophagy via OXR1-mediated ERK/mTOR signaling pathway |
title_full_unstemmed | Orexin-A exerts neuroprotective effect in experimental intracerebral hemorrhage by suppressing autophagy via OXR1-mediated ERK/mTOR signaling pathway |
title_short | Orexin-A exerts neuroprotective effect in experimental intracerebral hemorrhage by suppressing autophagy via OXR1-mediated ERK/mTOR signaling pathway |
title_sort | orexin-a exerts neuroprotective effect in experimental intracerebral hemorrhage by suppressing autophagy via oxr1-mediated erk/mtor signaling pathway |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9815810/ https://www.ncbi.nlm.nih.gov/pubmed/36619670 http://dx.doi.org/10.3389/fncel.2022.1045034 |
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