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Sevoflurane-Induced Neurotoxicity in the Developing Hippocampus via HIPK2/AKT/mTOR Signaling

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Abstract

Sevoflurane (Sev) is a widely used inhalational anesthetic for general anesthesia in children. Previous studies have confirmed that multiple exposures to inhaled anesthetic can induce long-term neurotoxicity in newborn mice. However, the underlying mechanisms remain elusive. In this study, we investigated the role of homeodomain interacting protein kinase 2 (HIPK2), a stress activating kinase involved in neural survival and synaptic plasticity, and its underlying mechanism in sevoflurane-induced neurotoxicity. Empirical study showed that neuronal apoptosis was elevated after exposure to sevoflurane. Meanwhile, up-regulation of HIPK2 and AKT/mTOR signaling was observed in primary hippocampal neurons and hippocampus in mice upon anesthetic exposure. A64, antagonist of HIPK2, could significantly reduce increased apoptosis and activation of AKT/mTOR induced by sevoflurane. AKT antagonist MK2206 partially alleviated neuronal apoptosis without affecting the expression of HIPK2. Experimental results demonstrated a crucial role of HIPK2/AKT/mTOR signaling in neurotoxicity of sevoflurane. Thus, HIPK2/AKT/mTOR signaling can serve as a potential target for the protection of inhalation anesthesia-induced cytotoxicity in the future.

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Acknowledgements

The authors thank Drs. Andi Cheng and Yuanyuan Zhu for their technical assistance.

Funding

This work was supported by National Natural Science Foundation of China to Dr. Hui Zhang (Grant No. 81971076, 81371265), Science Innovation Promoting Program of Shaanxi Province to Dr. Hui Zhang (Grant No. 2014KTCL0305), Natural Science of Shaanxi Province to Ms. Liang (Grant No. 2021JQ345), and National Natural Science Foundation of China to Ms. Liang (Grant No. 82101345).

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Author notes

  1. Lirong Liang, Ze Fan, and Danyi He contributed equally to the work.

Authors and Affiliations

  1. State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research, Center for Dental Materials and Advanced Manufacture, Department of Anethesiology, School of Stomatology, School of Stomatology, Fourth Military Medical University, Shaanxi, 710032, Xi’an, People’s Republic of China

    Lirong Liang, Ze Fan, Danyi He, Youyi Zhao, Tian Zeng, Bing Liu, Tianyuan Ma & Hui Zhang

  2. Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi, 710032, People’s Republic of China

    Junjun Kang

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  1. Lirong Liang
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Contributions

Flow cytometry apoptosis detection: L.L., F.Z. H.D.; immunohistochemistry: L.L., Z.Y., M.T.; Western blotting: L.L. K.J., F.Z.; data analysis: L.L., H.D., L.B.; manuscript preparation: L.L., Z.H.; experimental design: L.L., Z.H.; financial support: Z.H., L.L.

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Correspondence to Hui Zhang.

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All experimental procedures were carried out according to the protocols approved by the Animal Care and Use Committee of FMMU.

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Liang, L., Fan, Z., He, D. et al. Sevoflurane-Induced Neurotoxicity in the Developing Hippocampus via HIPK2/AKT/mTOR Signaling. Neurotox Res 40, 803–813 (2022). https://doi.org/10.1007/s12640-021-00445-8

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