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Fluoxetine alleviates postoperative cognitive dysfunction by attenuating TLR4/MyD88/NF-κB signaling pathway activation in aged mice

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Abstract

Objective and design

Postoperative cognitive dysfunction (POCD) is a common complication following surgery among elderly patients. Emerging evidence demonstrates that neuroinflammation plays a pivotal role in the pathogenesis of POCD. This study tested the hypothesis that fluoxetine can protect against POCD by suppressing hippocampal neuroinflammation through attenuating TLR4/MyD88/NF-κB signaling pathway activation.

Subjects

Aged C57BL/6 J male mice (18 months old) were studied.

Treatment

Aged mice were intraperitoneally injected with fluoxetine (10 mg/kg) or saline for seven days before splenectomy. In addition, aged mice received an intracerebroventricular injection of a TLR4 agonist or saline seven days before splenectomy in the rescue experiment.

Methods

On postoperative days 1, 3, and 7, we assessed hippocampus-dependent memory, microglial activation status, proinflammatory cytokine levels, protein levels related to the TLR4/MyD88/NF-κB signaling pathway, and hippocampal neural apoptosis in our aged mouse model.

Results

Splenectomy induced a decline in spatial cognition, paralleled by parameters indicating exacerbation of hippocampal neuroinflammation. Fluoxetine pretreatment partially restored the deteriorated cognitive function, downregulated proinflammatory cytokine levels, restrained microglial activation, alleviated neural apoptosis, and suppressed the increase in TLR4, MyD88, and p-NF-κB p65 in microglia. Intracerebroventricular injection of LPS (1 μg, 0.5 μg/μL) before surgery weakened the effect of fluoxetine.

Conclusion

Fluoxetine pretreatment suppressed hippocampal neuroinflammation and mitigated POCD by inhibiting microglial TLR4/MyD88/NF-κB pathway activation in aged mice.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This study was supported by the Medical Innovation Project of Fujian Province (Grant No. 2022CXA007), Fujian Medical University Startup Fund for scientific research (Grant No. 2020QH1162), the Natural Science Foundation of Fujian Province (Grant No. 2021J01378), and the National Natural Science Foundation of China (Grant No. 821711186).

Author information

Author notes

  1. Yusheng Yao and Daoyi Lin contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, No. 134, Dongjie, Fuzhou, 350001, Fujian, China

    Yusheng Yao, Daoyi Lin, Linwei Liu, Yushang Wu & Xiaochun Zheng

  2. Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China

    Yuzhi Chen

  3. Fujian Provincial Key Laboratory of Critical Care Medicine, Fuzhou, Fujian, China

    Yusheng Yao & Xiaochun Zheng

Authors
  1. Yusheng Yao
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  4. Linwei Liu
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  5. Yushang Wu
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Contributions

YY, DL, and XZ: conceived and designed the experiments. DL, LL, and YW: performed the experiments. YC and YW: analyzed the data. DL and YC: wrote the draft. YY and XZ: revised the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xiaochun Zheng.

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Yao, Y., Lin, D., Chen, Y. et al. Fluoxetine alleviates postoperative cognitive dysfunction by attenuating TLR4/MyD88/NF-κB signaling pathway activation in aged mice. Inflamm. Res. 72, 1161–1173 (2023). https://doi.org/10.1007/s00011-023-01738-8

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  • DOI: https://doi.org/10.1007/s00011-023-01738-8

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