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Nrf2 attenuates oxidative stress to mediate the protective effect of ciprofol against cerebral ischemia–reperfusion injury

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Abstract

Neuroinflammation and oxidative stress damage are involved in the pathogenesis of cerebral ischemia–reperfusion injury (CIRI). Ferroptosis emerged as a new player in the regulation of lipid peroxidation processes. This study aimed at exploring the potential involvement of ciprofol on ferroptosis-associated CIRI and subsequent neurological deficits in the mouse model of transient cerebral ischemia and reperfusion. Cerebral ischemia was built in male C57BL/6 J wild-type (WT) and Nrf2-knockout (Nrf2 KO) mice in the manner of middle cerebral artery occlusion (MCAO) followed by reperfusion. Ciprofol improved autonomic behavior, alleviated reactive oxygen species output and ferroptosis-induced neuronal death by nucleus transportation of NFE2 like BZIP transcription factor 2 (Nrf2) and the promotion of heme oxygenase 1 (Ho-1), solute carrier family 7 member 11 (SLC7A11/xCT), and glutathione peroxidase 4 (GPX4). Additionally, ciprofol improved neurological scores and reduced infarct volume, brain water content, and necrotic neurons. Cerebral blood flow in MCAO-treated mice was also improved. Furthermore, absence of Nrf2 abrogated the neuroprotective actions of ciprofol on antioxidant capacity and sensitized neurons to oxidative stress damage. In vitro, the primary-cultured cortical neurons from mice were pre-treated with oxygen–glucose deprivation/reperfusion (OGD/R), followed by ciprofol administration. Ciprofol effectively reversed OGD/R-induced ferroptosis and accelerated transcription of GPX4 and xCT. In conclusion, we investigated the ciprofol-induced inhibition effect of ferroptosis-sheltered neurons from lipid preoxidation in the pathogenesis of CIRI via Nrf2-xCT-GPX4 signaling pathway.

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Data availability

The data used to support the findings of this study are available from the corresponding authors upon request.

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Acknowledgements

The authors would like to acknowledge the reviewers for their helpful comments on this paper.

Funding

This work was supported by the Ningbo Health Technology Project (grant No.2023Y12), and the National Natural Science Foundation of China, China (Grant No. 81704180).

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Author notes

  1. Xia Liu contributed to this work.

Authors and Affiliations

  1. Department of Anesthesiology, The First Affiliated Hospital of Ningbo University, Zhejiang Province, Ningbo, 315000, China

    Xia Liu & Changshun Huang

  2. Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Province, Wenzhou, 325000, China

    Xia Liu, Miao Ren, Anqi Zhang & Junlu Wang

Authors
  1. Xia Liu
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  2. Miao Ren
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  3. Anqi Zhang
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  4. Changshun Huang
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Contributions

J.W. and C.H. are the corresponding authors and they performed study design; X.L., M.R. and A.Z. performed the experiments; X.L. analyzed the data; D.C. provided technical support; C.H revised the manuscript carefully; All authors read and approved the final paper.

Corresponding authors

Correspondence to Changshun Huang or Junlu Wang.

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This study was approved and consented to by the ethics committee of the First Affiliated Hospital of Ningbo University.

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Liu, X., Ren, M., Zhang, A. et al. Nrf2 attenuates oxidative stress to mediate the protective effect of ciprofol against cerebral ischemia–reperfusion injury. Funct Integr Genomics 23, 345 (2023). https://doi.org/10.1007/s10142-023-01273-z

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  • DOI: https://doi.org/10.1007/s10142-023-01273-z

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