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Nootkatone Improves Chronic Unpredictable Mild Stress-Induced Depressive-Like Behaviors by Repressing NF-κB/NLRP3-Mediated Neuroinflammation

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Chinese Journal of Integrative Medicine Aims and scope Submit manuscript

Abstract

Objective

To explore the effect of nootkatone (NKT) on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and the mechanism underlying NKT improving the depressive-like behaviors.

Methods

The CUMS-induced depression model was established in mice. Fifty mice were randomized into 5 groups (n=10) in accordance with a random number table: control group, CUMS group, CUMS + NKT (6 mg/kg) group, CUMS + NKT (12 mg/kg) group, and CUMS + ketamine group. From the 22th day, NKT (6 or 12 mg/kg) or ketamine (0.5 mg/kg) was given with intragastric administration every day for 21 days. Behavioral tests including forced swimming test (FST), tail suspension test (TST), sucrose preference test (SPT) and open-field test (OFT) were carried out. The mRNA and protein expressions of interleukin (IL)-1β, IL-18, IL-6, and tumor necrosis factor (TNF)-α in hippocampus were assessed using quantitative realtime polymerase chain reaction (PCR), Western blot analysis, and enzyme linked immunosorbent assay. The nuclear factor-κB (NF-κB)/NOD-like receptor 3 (NLRP3) inflammasome pathway was analyzed using Western blot and immunofluorescence analysis.

Results

NKT treatment improved CUMS-induced depressive-like behaviors in mice (P<0.05 or P<0.01). NKT significantly decreased the mRNA and protein levels of IL-1β, IL-18, IL-6, and TNF-α in hippocampus of CUMS mice (P<0.05 or P<0.01). Furthermore, NKT repressed CUMS-induced activation of NF-κB signaling and NLRP3 inflammasome (P<0.01). More important, Nigericin, a NLRP3 activator, destroyed the effect of NKT on repressing neuroinflammation and improving depressive-like behaviors (P<0.05 or P<0.01).

Conclusion

NKT ameliorates the depressive-like symptoms, in part by repressing NF-κB/NLRP3-mediated neuroinflammation.

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Authors and Affiliations

  1. Basic Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Xin-hua Zhao, Meng-huan Xia, Wen-ping Liu & Qing-qi Wang

  2. Geriatrics Department, Shanghai Mental Health Center, Shanghai, 200030, China

    Na An

  3. Hematological Department, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China

    Ji-zhang Bao

Authors
  1. Xin-hua Zhao
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  2. Na An
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  3. Meng-huan Xia
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  4. Wen-ping Liu
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  5. Qing-qi Wang
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  6. Ji-zhang Bao
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Contributions

Zhao XH, AN na, Xia MH, Liu WP, Bao JZ and Wang QQ conceived and designed the experiments, performed the experiments, analyzed the data, prepared the figures and/or tables and drafted the work or revised it critically for important content.

Corresponding author

Correspondence to Ji-zhang Bao.

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The authors declare that they have no competing interests.

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Data Accessibility

All data in our study are available in this manuscript.

Supported by the Future Plan of Shanghai Municipal Hospital of Traditional Chinese Medicine (2021) Inheritance Talent Project (No. WLJH2021ZY-MZY033), The Xinglin Inherit-patterned Talents Program of Shanghai University of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine (No. 10 (2019) of the Personnel Office of Shanghai University of TCM) “The Fourth Batch of Clinical Young and Middle-Aged Backbone Teachers’ Teaching Ability Improvement Plan”

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Zhao, Xh., An, N., Xia, Mh. et al. Nootkatone Improves Chronic Unpredictable Mild Stress-Induced Depressive-Like Behaviors by Repressing NF-κB/NLRP3-Mediated Neuroinflammation. Chin. J. Integr. Med. 29, 37–43 (2023). https://doi.org/10.1007/s11655-022-3725-2

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  • DOI: https://doi.org/10.1007/s11655-022-3725-2

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