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

Shao-Peng Lin,Sheng-Qiang Chen,Xiao-Hui Chen,Jing-Yi Bu,Li-Dong Zhu,Jia-Song Hu,Pei-Yi Lin,Qi Li,Shan Ye,Hao-Jun Liao,Jue-Xian Wei

doi:10.1038/s41401-021-00634-3

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.

Highlights

Cognitive impairments are common complication derive from neuroinflammation in sepsis[1, 2]
Western blot demonstrated that artemisinin suppressed nuclear translocation of nuclear factor kappa-B and the expression of pro-inflammatory cytokines by activating adenosine monophosphateactivated protein kinaseα1 (AMPKα1) pathway
Artemisinin is a potential therapeutic agent for sepsis-associated neuroinflammation and cognitive impairment, and its effect was probably mediated by the activation of AMPKα1 signalling pathway in microglia

Summary

Introduction

Cognitive impairments are common complication derive from neuroinflammation in sepsis[1, 2]. We recently reported that artemisinin protects neuronal HT-22 cells from oxidative injury by activating the Akt pathway[12]. This suggests that artemisinin has a potential therapeutic effect on nervous system diseases. The role of artemisinin in neuroinflammation and cognitive dysfunction associated with sepsis remains unknown. We evaluated the in vivo and in vitro therapeutic effects of artemisinin on neuroinflammation and cognitive dysfunction associated with sepsis. There is growing evidence that artemisinin possesses potent anti-inflammatory and immunoregulatory properties. We evaluate the possible protective effects and explore the underlying mechanism of artemisinin on cognitive impairment resulting from sepsis

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Results

Discussion

Conclusion