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PP2A-associated tau hyperphosphorylation was involved in sevoflurane induced neonatal neurotoxicity

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Abstract

Background

The effects of sevoflurane anesthesia on childhood neurodevelopment and adult brain function have attracted increasing scientific attentions. However, the exact mechanisms underlying hyperphosphorylation of tau protein in sevoflurane induced abnormalities in central nervous system (CNS) development, particularly in the hippocampus, have not been fully determined.

Methods

We utilized molecular biological and behavioral approaches to compare the changes in cognitive function in mice exposed to repeated sevoflurane during the neonatal stage, and to assess whether PP2A-associated tau hyperphosphorylation is involved in sevoflurane induced neonatal neurotoxicity.

Results

We reported that mice anesthetized with repeated sevoflurane during the neonatal period caused cognitive dysfunction during the adulthood. More importantly, we found that hyperphosphorylation of tau protein and decreased level of protein phosphatase 2A (PP2A) were detected in the hippocampus of mice after neonatal exposure of sevoflurane. Meanwhile, GSK-3β activity was found to be increased with repeated sevoflurane exposure, but not for more than 2 weeks.

Conclusion

Our results suggest that PP2A-associated hyperphosphorylation of tau protein might contribute to sevoflurane induced developmental neurotoxicity. These findings could provide a theoretical basis for the safely usage of sevoflurane in pediatric surgeries, and offer a valuable reference and potential therapeutic targets for the development of neuroprotective drugs.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (82101270, and 81974171), Innovative and Entrepreneurial Team of Jiangsu Province (JSSCTD202144), Natural Science Foundation of Jiangsu Province (BK20211382, and BK20210975), and China Postdoctoral Science Foundation (2021M701496).

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Author notes

  1. Chaoli Huang and Teng He contributed equally to this work

Authors and Affiliations

  1. Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China

    Chaoli Huang, Teng He, Di Wang, Zifeng Wu, Yuanyuan Wang, Hanyu Liu, Jiali Xu, Chun Yang & Cunming Liu

  2. State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Nanjing University, Nanjing, 210061, China

    Chaoli Huang & Guiquan Chen

Authors
  1. Chaoli Huang
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  2. Teng He
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  5. Yuanyuan Wang
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Correspondence to Guiquan Chen or Cunming Liu.

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Huang, C., He, T., Wang, D. et al. PP2A-associated tau hyperphosphorylation was involved in sevoflurane induced neonatal neurotoxicity. Psychopharmacology 239, 2799–2807 (2022). https://doi.org/10.1007/s00213-022-06161-1

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  • DOI: https://doi.org/10.1007/s00213-022-06161-1

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