Pinocembrin ameliorates intermittent hypoxia-induced neuroinflammation through BNIP3-dependent mitophagy in a murine mod
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RESEARCH
Open Access
Pinocembrin ameliorates intermittent hypoxia-induced neuroinflammation through BNIP3-dependent mitophagy in a murine model of sleep apnea Lin-Jing Gong1†, Xin-Yuan Wang2†, Wen-Yu Gu3* and Xu Wu1*
Abstract Background: Intermittent hypoxia (IH) caused by obstructive sleep apnea (OSA) leads to neuroinflammation. Pinocembrin has been shown to have neuroprotective effects, while the therapeutic functions under IH condition are still unknown. Methods: An OSA model was established by CIH exposure inside custom-made chambers. C57BL/6 mice were intraperitoneally injected with pinocembrin (40 mg/kg, i.p.) or vehicle (PBS containing 5% povidone; i.p.), and the changes of behavior on mice were detected by the Morris water maze test. Immunohistochemical staining, western blotting, immunofluorescence assays, and immunoprecipitation were used to investigate the association between NLRP3 inflammasome and BNIP3-dependent mitophagy. The mitochondrial morphology and mitophagosomes were detected under a transmission electron microscope. The detrimental effects of IH were tested by annexin VFITC/PI staining, Mito SOX Red staining, and JC-1 mitochondrial membrane potential assay. Results: In this study, our observations in vivo indicated that the administration of pinocembrin can restore spatial learning and memory ability and reduce neuronal apoptosis and hippocampal inflammation. Pinocembrin treatment significantly inhibited the formation of NLRP3 inflammasome and infiltration of microglia and enhanced BNIP3-mediated mitophagy in the hippocampus of IH mice. Additionally, our in vitro results show that pinocembrin protects microglial cells against IH-induced cytotoxicity by activating BNIP3-dependent mitophagy through the JNKERK signaling pathway. Conclusions: In summary, our findings demonstrated that pinocembrin can act as a potential therapeutic strategy for IH-induced neuroinflammation. Keywords: Pinocembrin, Neuroinflammation, Microglia, Obstructive sleep apnea (OSA), BNIP3, Mitophagy
* Correspondence: [email protected]; [email protected] † Lin-Jing Gong and Xin-Yuan Wang contributed equally to this work. 3 Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, No. 301, Yanchang Rd, Shanghai 200072, China 1 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Feng Lin Rd, Shanghai 200032, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in
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