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Nobiletin Ameliorates NLRP3 Inflammasome-Mediated Inflammation Through Promoting Autophagy via the AMPK Pathway

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Abstract

Multiple lines of evidence have shown that neuroinflammation and autophagy are highly involved in the process of depression. Nobiletin (NOB) displays neuroprotective effects and anti-depressant-like effects. Given the evidence that NOB exerts anti-inflammatory effects and regulates autophagy, we investigate the anti-neuroinflammatory properties and the effect of regulating the autophagy of NOB and subsequently uncover the potential anti-depressant mechanisms of NOB. The behavioral changes of rats were observed after prolonged lipopolysaccharide (LPS) treatment and NOB administration. Rat hippocampus and BV2 cells treated by LPS and NOB were evaluated. The methods of real-time PCR analysis, Western blot, immunostaining, and adenovirus transfection were employed to determine neuroinflammation, autophagic markers, and nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) activation. Our study showed LPS enhanced the expression of pro-inflammatory cytokines and NLRP3 inflammasome activation but inhibited autophagy in both rat hippocampus and BV2 cells. NOB significantly improved the behavioral deficits and ameliorated the neuroinflammation induced by LPS in rats. Furthermore, NOB promoted autophagy and attenuated NLRP3 inflammasome activation induced by LPS, involving in the process the adenosine monophosphate–activated protein kinase (AMPK) pathway. Neuroprotective and anti-depressant actions of NOB relied on its effects of promoting autophagy and suppressing the activation of NLRP3, in which process of AMPK pathway may be involved.

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Funding

This work was supported by the National Natural Science Foundation of China (grant number 81602846), the Chinese Society of Clinical Pharmacy Project of Wu Jieping Medical Foundation (grant number 320.6750.19090-8), the Taishan Scholar Project of Shandong Province (grant number tsqn201812159), and excellent youth foundation program for developing health by relying on science and education of Lianyungang (grant number QN1601).

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  1. Haidong Wang and Yujin Guo contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, The Affiliated Lianyungang Hospital of Xuzhou Medical University/The First People’s Hospital of Lianyungang, Lianyungang, 222000, People’s Republic of China

    Haidong Wang

  2. Affiliated Jining First People’s Hospital of Jining Medical University, Jining Medical University, No. 6, Jiankang Road, Jining, 272000, Shandong, People’s Republic of China

    Yujin Guo & Pei Jiang

  3. Department of Public Health, Jining Medical University, Jining, 272000, People’s Republic of China

    Yi Qiao

  4. Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China

    Jun Zhang

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  1. Haidong Wang
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Contributions

Conceptualization, P. Jiang; methodology, H.D. Wang and Y.J. Guo; formal analysis, H.D. Wang, Y. Qiao, and J. Zhang; writing-original draft preparation, H.D. Wang; writing-review and editing, P. Jiang; funding acquisition, P. Jiang. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Pei Jiang.

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Wang, H., Guo, Y., Qiao, Y. et al. Nobiletin Ameliorates NLRP3 Inflammasome-Mediated Inflammation Through Promoting Autophagy via the AMPK Pathway. Mol Neurobiol 57, 5056–5068 (2020). https://doi.org/10.1007/s12035-020-02071-5

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