Abstract
Neuroinflammation is one of the critical events in neurodegenerative diseases, whereas microglia play an important role in the pathogenesis of neuroinflammation. In this study, we investigated the effects of a natural sesquiterpene lactone, 6-O-angeloylplenolin (6-OAP), isolated from the traditional Chinese medicine Centipeda minima (L.) A.Br., on neuroinflammation and the underlying mechanisms. We showed that treatment with lipopolysaccharide (LPS) caused activation of BV2 and primary microglial cells and development of neuroinflammation in vitro, evidenced by increased production of inflammatory cytokines TNF-α and IL-1β, the phosphorylation and nuclear translocation of NF-κB, and the transcriptional upregulation of COX-2 and iNOS, leading to increased production of proinflammatory factors NO and PGE2. Moreover, LPS treatment induced oxidative stress through increasing the expression levels of NOX2 and NOX4. Pretreatment with 6-OAP (0.5−4 μM) dose-dependently attenuated LPS-induced NF-κB activation and oxidative stress, thus suppressed neuroinflammation in the cells. In a mouse model of LPS-induced neuroinflammation, 6-OAP (5−20 mg·kg−1·d−1, ip, for 7 days before LPS injection) dose-dependently inhibited the production of inflammatory cytokines, the activation of the NF-κB signaling pathway, and the expression of inflammatory enzymes in brain tissues. 6-OAP pretreatment significantly ameliorated the activation of microglia and astrocytes in the brains. 6-OAP at a high dose caused a much stronger antineuroinflammatory effect than dexamethansone (DEX). Furthermore, we demonstrated that 6-OAP pretreatment could inhibit LPS-induced neurite and synaptic loss in vitro and in vivo. In conclusion, our results demonstrate that 6-OAP exerts antineuroinflammatory effects and can be considered a novel drug candidate for the treatment of neuroinflammatory diseases.
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Acknowledgements
This work was supported by Guangzhou Science Technology and Innovation Commission Technology Research Projects (201805010005), the National Natural Science Foundation of China (81473740, 81673627, 81673946, 81802776), the National Science Fund for Distinguished Young Scholars (81525026), and the National Key Research and Development Program of China “Research and Development of Comprehensive Technologies on Chemical Fertilizer and Pesticide Reduction and Synergism” (2017YFD0201402).
Author contributions
YLZ, YMY, HFP, YXC and YQL designed the experiments, collected and analyzed the data, and drafted the paper. YLZ, SYL and DHH performed the cellular experiments, YLZ, SYL and DHH performed the molecular experiments, and YLZ, SX, SFW, WL and YQL participated in animal surgery and data collection. YLZ, QW, LH, HFP, YXC and YQL revised the paper. All authors have read and approved the final submitted paper.
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Zhou, Yl., Yan, Ym., Li, Sy. et al. 6-O-angeloylplenolin exerts neuroprotection against lipopolysaccharide-induced neuroinflammation in vitro and in vivo. Acta Pharmacol Sin 41, 10–21 (2020). https://doi.org/10.1038/s41401-019-0261-5
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DOI: https://doi.org/10.1038/s41401-019-0261-5
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