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Sevoflurane Offers Neuroprotection in a Cerebral Ischemia/Reperfusion Injury Rat Model Through the E2F1/EZH2/TIMP2 Regulatory Axis

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Abstract

Cerebral ischemia/reperfusion (I/R) injury contributes considerably to the poor prognosis in patients with ischemic stroke. This study is aimed to delineate the molecular mechanistic actions by which sevoflurane protects against cerebral I/R injury. A rat model of cerebral I/R injury was established and pre-treated with sevoflurane, in which hippocampal neuron apoptosis was found to be repressed and the level of E2F transcription factor 1 (E2F1) was observed to be down-regulated. Then, the up-regulated expression of E2F1 was validated in rats with cerebral I/R injury, responsible for stimulated neuron apoptosis. Further, the binding of E2F1 to enhancer of zeste homolog 2 (EZH2) and EZH2 to tissue inhibitor of metalloproteinases-2 (TIMP2) was identified. The stimulative effect of the E2F1/EZH2/TIMP2 regulatory axis on neuron apoptosis was subsequently demonstrated through functional assays. After that, it was substantiated in vivo that sevoflurane suppressed the apoptosis of hippocampal neurons in rats with cerebral I/R injury by down-regulating E2F1 to activate the EZH2/TIMP2 axis. Taken together, our data elucidated that sevoflurane reduced neuron apoptosis through mediating the E2F1/EZH2/TIMP2 regulatory axis, thus protecting rats against cerebral I/R injury.

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Data Availability

The datasets generated/analyzed during the current study are available.

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Authors and Affiliations

  1. Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, No.1, Jianshe East Road, Zhengzhou, 450052, People’s Republic of China

    Lihua Yang, Hongfei Chen, Lina Guan & Yucan Xu

Authors
  1. Lihua Yang
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  2. Hongfei Chen
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  3. Lina Guan
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  4. Yucan Xu
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Contributions

Lihua Yang, Hongfei Chen, Lina Guan and Yucan Xu designed the study. Lihua Yang collated the data, designed and developed the database, carried out data analyses and produced the initial draft of the manuscript. Lihua Yang, Hongfei Chen and Lina Guan contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

Corresponding author

Correspondence to Yucan Xu.

Ethics declarations

Animal experiments were approved by the Animal Care and Use Committee of The First Affiliated Hospital of Zhengzhou University (Ethical Approval Number: 2018-063A) and performed in accordance with Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health.

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The authors declare no competing interests.

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Yang, L., Chen, H., Guan, L. et al. Sevoflurane Offers Neuroprotection in a Cerebral Ischemia/Reperfusion Injury Rat Model Through the E2F1/EZH2/TIMP2 Regulatory Axis. Mol Neurobiol 59, 2219–2231 (2022). https://doi.org/10.1007/s12035-021-02602-8

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  • DOI: https://doi.org/10.1007/s12035-021-02602-8

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