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Orexin-A protects against cerebral ischemia-reperfusion injury by inhibiting excessive autophagy through OX1R-mediated MAPK/ERK/mTOR pathway

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Xu, Dandan, Kong, Tingting, Zhang, Shengnan, Cheng, Baohua, Chen, Jing and Wang, Chunmei (2021) Orexin-A protects against cerebral ischemia-reperfusion injury by inhibiting excessive autophagy through OX1R-mediated MAPK/ERK/mTOR pathway. Cellular Signalling, 79 . 109839. doi:10.1016/j.cellsig.2020.109839

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Official URL: http://dx.doi.org/10.1016/j.cellsig.2020.109839

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Abstract

Orexin A (OXA) is a neuroprotective peptide that exerts protective effects on multiple physiological and pathological processes. Activation of autophagy is linked to the occurrence of cerebral ischemia–reperfusion injury (CIRI); however, its function remains incompletely understood. In this study, OXA was sought to exert its neuroprotective role by regulating autophagy in oxygen and glucose deprivation and reoxygenation (OGD/R) model and middle cerebral artery occlusion (MCAO) model of rats, and to elucidate the underlying molecular mechanisms. Acridine orange (AO) staining was used to evaluate autophagic vacuoles. Cell viability was measured by CCK8. The levels of p-ERK1/2, t-ERK1/2, p-mTOR, LC3B, Beclin 1, and p62 were evaluated by western blotting. Apoptosis rate was detected by Hoechst 33342 staining and Terminal deoxynucleotidyltransferase–mediated dUTP nick-end labeling (TUNEL). OXA treatment alleviated neuronal apoptosis and significantly inhibited autophagy activity. Mechanistically, OXA exerted its neuroprotective effects in vivo and in vitro by suppressing over-activated autophagy by modulating OX1R-mediated MAPK/ERK/mTOR pathway. The results of this study elucidate the roles of autophagy in CIRI and the mechanisms underlying the neuroprotective action of OXA. Our findings could facilitate the development of novel therapeutics for ischemic stroke.

Item Type: Journal Article
Subjects: Q Science > QH Natural history
Q Science > QP Physiology
R Medicine > RC Internal medicine
Divisions: Faculty of Medicine > Warwick Medical School > Biomedical Sciences
Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine
Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Orexins , Cell death , Cerebral ischemia , Oxygen -- Physiological transport , Neuroprotective agents
Journal or Publication Title: Cellular Signalling
Publisher: Elsevier
ISSN: 0898-6568
Official Date: March 2021
Dates:
DateEvent
March 2021Published
16 November 2020Available
13 November 2020Accepted
Volume: 79
Article Number: 109839
DOI: 10.1016/j.cellsig.2020.109839
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
JYHL2019ZD02Jining Medical Universityhttp://dx.doi.org/10.13039/501100008853

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