Sevoflurane post-conditioning alleviates neonatal rat hypoxic-ischemic cerebral injury via Ezh2-regulated autophagy
Authors Xue H, Xu Y, Wang S, Wu ZY, Li XY, Zhang YH, Niu JY, Gao QS, Zhao P
Received 6 December 2018
Accepted for publication 4 March 2019
Published 15 May 2019 Volume 2019:13 Pages 1691—1706
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Amy Norman
Peer reviewer comments 2
Editor who approved publication: Dr Qiongyu Guo
Hang Xue, Ying Xu, Shuo Wang, Zi-Yi Wu, Xing-Yue Li, Ya-Han Zhang, Jia-Yuan Niu, Qiu-Shi Gao, Ping Zhao
Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang 110004, People’s Republic of China
Background: When neonatal rats suffer hypoxic-ischemic brain injury (HIBI), autophagy is over-activated in the hippocampus, and inhibition of autophagy provides neuroprotection. The aim of this study was to investigate the possible roles of autophagy and Ezh2-regulated Pten/Akt/mTOR pathway in sevoflurane post-conditioning (SPC)-mediated neuroprotection against HIBI in neonatal rats.
Methods: Seven-day-old Sprague–Dawley rats underwent left common artery ligation followed by 2 h hypoxia as described in the Rice–Vannucci model. The roles of autophagy and the Ezh2-regulated Pten/Akt/mTOR signaling pathway in the neuroprotection conferred by SPC were examined by left-side intracerebroventricular injection with the autophagy activator rapamycin and the Ezh2 inhibitor GSK126.
Results: SPC was neuroprotective against HIBI through the inhibition of over-activated autophagy in the hippocampus as characterized by the rapamycin-induced reversal of neuronal density, neuronal morphology, cerebral morphology, and the expression of the autophagy markers, LC3B-II and Beclin1. SPC significantly increased the expression of Ezh2, H3K27me3, pAkt, and mTOR and decreased the expression of Pten induced by HI. The Ezh2 inhibitor, GSK126, significantly reversed the SPC-induced changes in expression of H3K27me3, Pten, pAkt, mTOR, LC3B-II, and Beclin1. Ezh2 inhibition also reversed SPC-mediated attenuation of neuronal loss and behavioral improvement in the Morris water maze.
Conclusion: These results indicate that SPC inhibits excessive autophagy via the regulation of Pten/Akt/mTOR signaling by Ezh2 to confer neuroprotection against HIBI in neonatal rats.
Keywords: sevoflurane post-conditioning, hypoxic-ischemic brain injury, neonatal rat, autophagy, Ezh2, Pten/Akt/mTOR
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