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mTORC1-Dependent and GSDMD-Mediated Pyroptosis in Developmental Sevoflurane Neurotoxicity

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Abstract

Developmental sevoflurane exposure leads to neuronal cell death, and subsequent learning and memory cognitive defects. The underlyi\ng mechanism remains to be elucidated. Gasdermin D (GSDMD)-mediated pyroptosis is a form of inflammatory cell death and participates in a variety of neurodegenerative diseases. Several studies illustrated that dysregulation of mTOR activity is involved in pyroptotic cell death. The current study was designed to interrogate the role of GSDMD-mediated pyroptosis and mTOR activity in developmental sevoflurane exposure. We found that inhibition of GSDMD pore formation with Disulfiram (DSF) or Necrosulfonamide (NSA) significantly attenuated sevoflurane neurotoxicity in vitro. In addition, treatment with DSF or NSA also mitigated damage-associated molecular patterns (DAMPs) release and subsequent plasma membrane rupture (PMR) induced by sevoflurane challenge. Further investigation showed that the overactivation of mTOR signaling is involved in sevoflurane induced pyroptosis both in vivo and in vitro. Intriguingly, we found that the DAMPs release and subsequent PMR triggered by developmental sevoflurane priming were compromised by knocking down the expression of mTORC1 component Raptor, but not mTORC2 component Rictor. Moreover, sevoflurane induced pyroptosis could also be restored by suppressing mTOR activity or knocking down the expressions of Ras-related small GTPases RagA or RagC. Finally, administration of DSF or NSA dramatically improved the spatial and emotional cognitive disorders without alternation of locomotor activity. Taken together, these results indicate that mTORC1-dependent and GSDMD-mediated pyroptosis contributes to the developmental sevoflurane neurotoxicity. Characterizing these processes may provide experimental evidence for the possible prevention of developmental sevoflurane neurotoxicity.

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Data Availability

All data generated or analyzed during this study are included in this published article and are available from the corresponding author on reasonable request.

Abbreviations

4E-BP1:

EIF-4E binding protein-1

CNS:

Central nervous system

DAMPs:

Damage-associated molecular patterns

DSF:

Disulfiram

GSDMD:

Gasdermin D

HMGB1:

High-mobility group box 1

LDH:

Lactate dehydrogenase

mTOR:

Mammalian target of rapamycin

MWM:

Morris water maze

NINJ1:

Ninjurin-1

NSA:

Necrosulfonamide

PMR:

Plasma membrane rupture

S6K1:

P70 ribosomal protein S6 kinase 1

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Acknowledgements

The authors wish to thank Luo Fo-Quan and Hong Hua-li for critical comments on this topic.

Funding

This research was supported by the Zhejiang Provincial Natural Science Foundation of China under Grant No. LY18H310007 (Wen-Yuan Wang), and the National Natural Science Foundation, Beijing, China, grant No. 81302858 (Wen-Yuan Wang), the National Key Research and Development Program of China (No. 2018YFC2001904) and the Zhejiang Provincial Science and Technology Project (No. 2023574725).

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Authors and Affiliations

  1. Center for Rehabilitation Medicine, Department of Anesthesiology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China

    Wang Wen-Yuan, Qian Shao-Jie, Liu Jin-Tao, Mao Hui & Cai Fang

  2. Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China

    Yi Wan-Qing, Hu Qi-Yun & Liu Yu-Si

  3. Department of Anesthesiology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, 310023, China

    Yang Hui-Ling

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  1. Wang Wen-Yuan
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Contributions

WWY designed the study, conducted the majority of the experiments and wrote most of the manuscript. YWQ prepared neuronal cultures and wrote the preliminary manuscript. HQY and LYS helped with western blot analysis. QSJ and LJT performed the behavior study. MH and CF carried out FCM and immunofluorescence. YHL performed confocal microscopy, analyzed the results, edited the manuscript and contributed to the supervision of the study. All authors approved the version to be published.

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Correspondence to Wang Wen-Yuan or Yang Hui-Ling.

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All animal experiments and protocol have been approved by the Animal Care and Use Committee of Zhejiang Provincial People’s Hospital (Affiliated People`s Hospital, Hangzhou Medical College).

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Wen-Yuan, W., Wan-Qing, Y., Qi-Yun, H. et al. mTORC1-Dependent and GSDMD-Mediated Pyroptosis in Developmental Sevoflurane Neurotoxicity. Mol Neurobiol 60, 116–132 (2023). https://doi.org/10.1007/s12035-022-03070-4

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