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Artemisinin improves neurocognitive deficits associated with sepsis by activating the AMPK axis in microglia

Abstract

Sepsis is life-threatening organ dysfunction due to dysregulated systemic inflammatory and immune response to infection, often leading to cognitive impairments. Growing evidence shows that artemisinin, an antimalarial drug, possesses potent anti-inflammatory and immunoregulatory activities. In this study we investigated whether artemisinin exerted protective effect against neurocognitive deficits associated with sepsis and explored the underlying mechanisms. Mice were injected with LPS (750 μg · kg−1 · d−1, ip, for 7 days) to establish an animal model of sepsis. Artemisinin (30 mg · kg−1 · d−1, ip) was administered starting 4 days prior LPS injection and lasting to the end of LPS injection. We showed that artemisinin administration significantly improved LPS-induced cognitive impairments assessed in Morris water maze and Y maze tests, attenuated neuronal damage and microglial activation in the hippocampus. In BV2 microglial cells treated with LPS (100 ng/mL), pre-application of artemisinin (40 μΜ) significantly reduced the production of proinflammatory cytokines (i.e., TNF-α, IL-6) and suppressed microglial migration. Furthermore, we revealed that artemisinin significantly suppressed the nuclear translocation of NF-κB and the expression of proinflammatory cytokines by activating the AMPKα1 pathway; knockdown of AMPKα1 markedly abolished the anti-inflammatory effects of artemisinin in BV2 microglial cells. In conclusion, atemisinin is a potential therapeutic agent for sepsis-associated neuroinflammation and cognitive impairment, and its effect is probably mediated by activation of the AMPKα1 signaling pathway in microglia.

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Fig. 1: Artemisinin improved cognitive impairment in an LPS-induced sepsis model.
Fig. 2: Artemisinin ameliorated neuronal cell death in an LPS-induced murine sepsis model.
Fig. 3: Artemisinin attenuated LPS-induced microglial activation in the hippocampus.
Fig. 4: The effects of artemisinin on proinflammatory cytokines in BV2 microglia.
Fig. 5: Artemisinin preconditioning reduced LPS-induced upregulation of the mRNA and protein expression of IL-6 and TNF-α.
Fig. 6: Artemisinin inhibited the migratory ability of BV2 microglia.
Fig. 7: Artemisinin activates AMPKα1 and suppresses the inflammatory response in BV2 cells.
Fig. 8: The anti-inflammatory effect of artemisinin on LPS-stimulated BV2 microglia was blocked by AMPKα1-specific siRNA.
Fig. 9: The possible neuroprotective mechanism of artemisinin in sepsis-associated neuroinflammation.

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Acknowledgements

This work was partly supported by the National Natural Science Foundation of China (Grant No. 81641088), the Natural Science Foundation of Guangdong Province (Grant No. 2017B030311019), the Science and Technology Planning Project of Guangdong Province (Grant No. 2015A030302091), the Science and Technology Planning Project of Guangzhou (Grant No. 201607010160), and the Key Medical Disciplines and Specialties Program of Guangzhou (2017-2019). Guangzhou Institute of Cardiovascular Disease, the Second Affiliated Hospital of Guangzhou Medical University, provided us with some experimental instruments.

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XHC, PYL, and SPL designed the experiments. JXW, JSH, JYB, LDZ, QL, HJL, and SQC conducted the experiments. SPL and SY wrote the manuscript. All the authors analyzed the data, revised the manuscript, and approved the final manuscript.

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Correspondence to Xiao-hui Chen.

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Lin, Sp., Wei, Jx., Hu, Js. et al. Artemisinin improves neurocognitive deficits associated with sepsis by activating the AMPK axis in microglia. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00634-3

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Keywords

  • artemisinin
  • sepsis
  • cognitive dysfunction
  • neuroinflammation
  • microglia
  • AMP-activated protein kinases

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