Nobiletin Ameliorates NLRP3 Inflammasome-Mediated Inflammation Through Promoting Autophagy via the AMPK Pathway
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Nobiletin Ameliorates NLRP3 Inflammasome-Mediated Inflammation Through Promoting Autophagy via the AMPK Pathway Haidong Wang 1 & Yujin Guo 2 & Yi Qiao 3 & Jun Zhang 4 & Pei Jiang 2 Received: 14 May 2020 / Accepted: 11 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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 antiinflammatory 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. Keywords AMPK . Autophagy . Depression . NLRP3 . Nobiletin
Introduction Depression is a major human blight characterized by depressive mood or loss of interest or pleasure for the major part of the day. The global prevalence of depression is high, and over 264 million people of the world’s population suffer from depression according to the World Health Organization [1]. The Haidong Wang and Yujin Guo contributed equally to this work. * Pei Jiang [email protected] 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
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
3
Department of Public Health, Jining Medical University, Jining 272000, People’s Republic of China
4
Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
figures are substantial, but it is likely an underestimate of the actual prevalence of depression due to the social and cultural stigma ab
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