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Sevoflurane Postconditioning Inhibits Autophagy Through Activation of the Extracellular Signal-Regulated Kinase Cascade, Alleviating Hypoxic-Ischemic Brain Injury in Neonatal Rats

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Abstract

Hypoxic-ischemic brain injury (HIBI) in neonates is one of the major contributors of newborn death and cognitive impairment. Numerous animal studies have demonstrated that autophagy is substantially increased in HIBI and that sevoflurane postconditioning (SPC) can attenuate HIBI. However, if SPC-induced neuroprotection inhibits autophagy in HIBI remains unknown. To investigate if cerebral protection induced by SPC is related to decreased autophagy in the setting of HIBI. Postnatal rats at day 7 (P7) were randomly assigned to 7 different groups: Sham, HIBI, SPC–HIBI, HIBI + rapamycin, SPC–HIBI + rapamycin, HIBI + p-extracellular signal-regulated kinase (p-ERK) inhibitor, and SPC–HIBI + p-ERK inhibitor. To induce HIBI, neonatal rats underwent left common carotid artery ligation, followed by 2 h of hypoxia (8% O2). Rats in the SPC groups were treated with 1 minimum alveolar concentration ([MAC], 2.4%) SPC for 30 min after HIBI induction. Markers of autophagy and expression of ERK cascade components were measured in the rat brains after 24 h. Spatial learning and memory function were examined 29–34 days after administration of an autophagy agonist or a p-ERK inhibitor. The expression of microtubule-associated proteins 1A/1B, light chain 3B II (LC3-II) and tuberous sclerosis complex 2 (TSC2) were decreased in the SPC–HIBI group compared to the HIBI group. Expression of the p62 sequestosome 1 (P62/SQSTM1) protein, p-ERK/ERK, phospho-mammalian target of rapamycin (p-mTOR) and phospho-p70S6 were increased in SPC–HIBI group. Rats within the SPC–HIBI groups that also received the p-ERK inhibitor or autophagy inhibitor demonstrated reduced cross platform times and increased escape latency. Approximately 30 min of 2.4% SPC treatment in the P7 rat HIBI model attenuated excessive autophagy in the brain by elevating the ERK cascade. This finding provides additional insight into HIBI and identifies new targets for therapeutic approaches to treat HIBI.

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Abbreviations

HIBI:

Hypoxic-ischemic brain injury

SPC:

Sevoflurane postconditioning

ERK:

Extracellular signal-regulated kinase

ERKI:

ERK inhibitor

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Funding

This study was supported by two grants from the National Natural Science Foundation of China (Nos. 81171782, 81671311), one grant from Science and Technology foundation of Liaoning province (No. 2015020467), one grant from the Outstanding Scientific Fund of Shengjing Hospital (No. 201708).

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Authors and Affiliations

  1. Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, 110004, People’s Republic of China

    Shuo Wang, Hang Xue, Ying Xu, Jiayuan Niu & Ping Zhao

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  1. Shuo Wang
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  2. Hang Xue
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  3. Ying Xu
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  4. Jiayuan Niu
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  5. Ping Zhao
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Contributions

SW and PZ designed the experiments. SW, HX and PZ contributed to the planning of the work. SW performed all the experiments with the help of HX, YX and JN. HX, YX and JN participated in the data collection. SW, YX and JN analyzed and interpreted the results. SW wrote the manuscript with the help of YX. PZ supervised the project and revised the article.

Corresponding author

Correspondence to Ping Zhao.

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The authors declare that they have no conflict of interest.

Ethics Approval

All animal experiments were carried out in accordance with the National Institute of Health Guideline for the Care and Use of Laboratory Animals. Formal approval to conduct the experiments described has been obtained from the animal review board of Shengjing Hospital, China Medical University.

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Wang, S., Xue, H., Xu, Y. et al. Sevoflurane Postconditioning Inhibits Autophagy Through Activation of the Extracellular Signal-Regulated Kinase Cascade, Alleviating Hypoxic-Ischemic Brain Injury in Neonatal Rats. Neurochem Res 44, 347–356 (2019). https://doi.org/10.1007/s11064-018-2682-9

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