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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Annane D, Sharshar T. Cognitive decline after sepsis. Lancet Respir Med. 2015;3:61–9.
Zhang LN, Wang XT, Ai YH, Guo QL, Huang L, Liu ZY, et al. Epidemiological features and risk factors of sepsis-associated encephalopathy in intensive care unit patients: 2008-11. Chin Med J. 2012;125:828–31.
Silva AYO, Amorim EA, Barbosa-Silva MC, Lima MN, Oliveira HA, Granja MG, et al. Mesenchymal stromal cells protect the blood-brain barrier, reduce astrogliosis, and prevent cognitive and behavioral alterations in surviving septic mice. Crit Care Med. 2020;48:e290–e98.
Zong MM, Zhou ZQ, Ji MH, Jia M, Tang H, Yang JJ. Activation of β2-adrenoceptor attenuates sepsis-induced hippocampus-dependent cognitive impairments by reversing neuroinflammation and synaptic abnormalities. Front Cell Neurosci. 2019;13:293.
Widmann CN, Heneka MT. Long-term cerebral consequences of sepsis. Lancet Neurol. 2014;13:630–6.
Sonneville R, de Montmollin E, Poujade J, Garrouste-Orgeas M, Souweine B, Darmon M, et al. Potentially modifiable factors contributing to sepsis-associated encephalopathy. Intensive Care Med. 2017;43:1075–84.
Tu Y. Artemisinin—a gift from traditional chinese medicine to the world (Nobel Lecture). Angew Chem Int Ed Engl. 2016;55:10210–26.
Miller LH, Su X. Artemisinin: discovery from the Chinese herbal garden. Cell. 2011;146:855–8.
Das AK. Anticancer effect of antimalarial artemisinin compounds. Ann Med Health Sci Res. 2015;5:93–102.
Chen W, Li FF, Li C, Sui JK, Meng QF, Li XL, et al. Artemisinin ameliorates the symptoms of experimental autoimmune myasthenia gravis by regulating the balance of TH1 cells, TH17 cells and Treg cells. J Biol Regul Homeost Agents. 2018;32:1217–23.
Tilaoui M, Mouse HA, Jaafari A, Zyad A. Differential effect of artemisinin against cancer cell lines. Nat Prod Bioprospect. 2014;4:189–96.
Liu X, Lu J, Liao Y, Liu S, Chen Y, He R, et al. Dihydroartemisinin attenuates lipopolysaccharide-induced acute kidney injury by inhibiting inflammation and oxidative stress. Biomed Pharmacother. 2019;117:109070.
Lin SP, Li W, Winters A, Liu R, Yang SH. Artemisinin prevents glutamate-induced neuronal cell death via Akt pathway activation. Front Cell Neurosci. 2018;12:108.
Yao Y, Guo Q, Cao Y, Qiu Y, Tan R, Yu Z, et al. Artemisinin derivatives inactivate cancer-associated fibroblasts through suppressing TGF-beta signaling in breast cancer. J Exp Clin Cancer Res. 2018;37:282.
Xie LH, Li Q, Zhang J, Weina PJ. Pharmacokinetics, tissue distribution and mass balance of radiolabeled dihydroartemisinin in male rats. Malar J. 2009;8:112.
Wang BN, Wu CB, Chen ZM, Zheng PP, Liu YQ, Xiong J, et al. DL-3-n-butylphthalide ameliorates diabetes-associated cognitive decline by enhancing PI3K/Akt signaling and suppressing oxidative stress. Acta Pharmacol Sin. 2021;42:347–60.
National Research Council (U.S.). Committee for the update of the Guide for the Care and Use of Laboratory Animals., Institute for Laboratory Animal Research (U.S.), National Academies Press (U.S.). Guide for the care and use of laboratory animals. 8th ed. Washington, D.C.: National Academies Press; 2011.
Shrum B, Anantha RV, Xu SX, Donnelly M, Haeryfar SM, McCormick JK, et al. A robust scoring system to evaluate sepsis severity in an animal model. BMC Res Notes. 2014;7:233.
Zhou R, Yang X, Li X, Qu Y, Huang Q, Sun X, et al. Recombinant CC16 inhibits NLRP3/caspase-1-induced pyroptosis through p38 MAPK and ERK signaling pathways in the brain of a neonatal rat model with sepsis. J Neuroinflammation. 2019;16:239.
Zhao J, Bi W, Xiao S, Lan X, Cheng X, Zhang J, et al. Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Sci Rep. 2019;9:5790.
Vargas-Caraveo A, Sayd A, Robledo-Montana J, Caso JR, Madrigal JLM, Garcia-Bueno B, et al. Toll-like receptor 4 agonist and antagonist lipopolysaccharides modify innate immune response in rat brain circumventricular organs. J Neuroinflammation. 2020;17:6.
Young K, Morrison H. Quantifying microglia morphology from photomicrographs of immunohistochemistry prepared tissue using ImageJ. J Vis Exp. 2018;136:57648.
Jung EH, Hwang JS, Kwon MY, Kim KH, Cho H, Lyoo IK, et al. A tryptamine-paeonol hybridization compound inhibits LPS-mediated inflammation in BV2 cells. Neurochem Int. 2016;100:35–43.
Park J, Ha SH, Abekura F, Lim H, Chang YC, Lee MJ, et al. 4-O-carboxymethylascochlorin protected against microglial-mediated neurotoxicity in SH-SY5Y and BV2 cocultured cells from LPS-induced neuroinflammation and death by inhibiting MAPK, NF-kappaB, and Akt pathways. J Cell Biochem. 2018;120:1742–53.
Lin SP, Ye S, Chen XH, Jiang HL, Mao HF, Chen MT, et al. Increased expression of microRNA-21 in peripheral blood mediates the down-regulation of IFN-gamma and increases the prevalence of stroke-associated infection. J Neurol Sci. 2016;366:235–9.
Lin SP, Ye S, Long Y, Fan Y, Mao HF, Chen MT, et al. Circular RNA expression alterations are involved in OGD/R-induced neuron injury. Biochem Biophys Res Commun. 2016;471:52–6.
Peng X, Wang Y, Li H, Fan J, Shen J, Yu X, et al. ATG5-mediated autophagy suppresses NF-kappaB signaling to limit epithelial inflammatory response to kidney injury. Cell Death Dis. 2019;10:253.
Ponomarev ED, Shriver LP, Maresz K, Dittel BN. Microglial cell activation and proliferation precedes the onset of CNS autoimmunity. J Neurosci Res. 2005;81:374–89.
Cao Q, Du H, Fu X, Duan N, Liu C, Li X. Artemisinin attenuated atherosclerosis in high-fat diet-Fed ApoE−/− mice by promoting macrophage autophagy through the AMPK/mTOR/ULK1 pathway. J Cardiovasc Pharmacol. 2020;75:321–32.
Li S, Zhao X, Lazarovici P, Zheng W. Artemether activation of AMPK/GSK3beta(ser9)/Nrf2 signaling confers neuroprotection towards beta-amyloid-induced neurotoxicity in 3xTg Alzheimer’s mouse model. Oxid Med Cell Longev. 2019;2019:1862437.
Stubbs DJ, Yamamoto AK, Menon DK. Imaging in sepsis-associated encephalopathy-insights and opportunities. Nat Rev Neurol. 2013;9:551–61.
Schedlowski M, Engler H, Grigoleit JS. Endotoxin-induced experimental systemic inflammation in humans: a model to disentangle immune-to-brain communication. Brain Behav Immun. 2014;35:1–8.
Qiang W, Cai W, Yang Q, Yang L, Dai Y, Zhao Z, et al. Artemisinin B improves learning and memory impairment in AD dementia mice by suppressing neuroinflammation. Neuroscience. 2018;395:1–12.
Lemstra AW, Groen in’t Woud JC, Hoozemans JJ, van Haastert ES, Rozemuller AJ, Eikelenboom P. et al. Microglia activation in sepsis: a case-control study. J Neuroinflammation. 2007;4:4.
Pan C, Si Y, Meng Q, Jing L, Chen L, Zhang Y, et al. Suppression of the RAC1/MLK3/p38 signaling pathway by beta-elemene alleviates sepsis-associated encephalopathy in mice. Front Neurosci. 2019;13:358.
Beggs S, Salter MW. SnapShot: microglia in disease. Cell. 2016;165:1294–94.e1.
Sui DM, Xie Q, Yi WJ, Gupta S, Yu XY, Li JB, et al. Resveratrol protects against sepsis-associated encephalopathy and inhibits the NLRP3/IL-1beta axis in microglia. Mediators Inflamm. 2016;2016:1045657.
Zhu C, Xiong Z, Chen X, Peng F, Hu X, Chen Y, et al. Artemisinin attenuates lipopolysaccharide-stimulated proinflammatory responses by inhibiting NF-kappaB pathway in microglia cells. PLoS ONE. 2012;7:e35125.
Block ML, Calderon-Garciduenas L. Air pollution: mechanisms of neuroinflammation and CNS disease. Trends Neurosci. 2009;32:506–16.
Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405.
Xanthos DN, Sandkuhler J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci. 2014;15:43–53.
Tang Y, Le W. Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol. 2016;53:1181–94.
Wang YW, Zhou Q, Zhang X, Qian QQ, Xu JW, Ni PF, et al. Mild endoplasmic reticulum stress ameliorates lipopolysaccharide-induced neuroinflammation and cognitive impairment via regulation of microglial polarization. J Neuroinflammation. 2017;14:233.
Piao HZ, Choi IY, Park JS, Kim HS, Cheong JH, Son KH, et al. Wogonin inhibits microglial cell migration via suppression of nuclear factor-kappa B activity. Int Immunopharmacol. 2008;8:1658–62.
Fang Y, Wang J, Yao L, Li C, Wang J, Liu Y, et al. The adhesion and migration of microglia to beta-amyloid (Abeta) is decreased with aging and inhibited by Nogo/NgR pathway. J Neuroinflammation. 2018;15:210.
Scheiblich H, Bicker G. Regulation of microglial migration, phagocytosis, and neurite outgrowth by HO-1/CO signaling. Dev Neurobiol. 2015;75:854–76.
Lecca D, Janda E, Mulas G, Diana A, Martino C, Angius F, et al. Boosting phagocytosis and anti-inflammatory phenotype in microglia mediates neuroprotection by PPARgamma agonist MDG548 in Parkinson’s disease models. Br J Pharmacol. 2018;175:3298–314.
Vinoth Kumar R, Oh TW, Park YK. Anti-inflammatory effects of ginsenoside-Rh2 inhibits LPS-induced activation of microglia and overproduction of inflammatory mediators via modulation of TGF-beta1/Smad pathway. Neurochem Res. 2016;41:951–7.
Su F, Bai F, Zhang Z. Inflammatory cytokines and Alzheimer’s disease: a review from the perspective of genetic polymorphisms. Neurosci Bull. 2016;32:469–80.
Luo L, Wu J, Qiao L, Lu G, Li J, Li D. Sestrin 2 attenuates sepsis-associated encephalopathy through the promotion of autophagy in hippocampal neurons. J Cell Mol Med. 2020;24:6634–43.
Zhuang X, Yu Y, Jiang Y, Zhao S, Wang Y, Su L, et al. Molecular hydrogen attenuates sepsis-induced neuroinflammation through regulation of microglia polarization through an mTOR-autophagy-dependent pathway. Int Immunopharmacol. 2020;81:106287.
Lin SC, Hardie DG. AMPK: sensing glucose as well as cellular energy status. Cell Metab. 2018;27:299–313.
Garcia D, Shaw RJ. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell. 2017;66:789–800.
Jiang T, Yu JT, Zhu XC, Wang HF, Tan MS, Cao L, et al. Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre-activation of AMPK-dependent autophagy. Br J Pharmacol. 2014;171:3146–57.
Jian M, Kwan JS, Bunting M, Ng RC, Chan KH. Adiponectin suppresses amyloid-beta oligomer (AbetaO)-induced inflammatory response of microglia via AdipoR1-AMPK-NF-kappaB signaling pathway. J Neuroinflammation. 2019;16:110.
Cacicedo JM, Yagihashi N, Keaney JF Jr, Ruderman NB, Ido Y. AMPK inhibits fatty acid-induced increases in NF-kappaB transactivation in cultured human umbilical vein endothelial cells. Biochem Biophys Res Commun. 2004;324:1204–9.
Thirupathi A, de Souza CT. Multi-regulatory network of ROS: the interconnection of ROS, PGC-1 alpha, and AMPK-SIRT1 during exercise. J Physiol Biochem. 2017;73:487–94.
Afonina IS, Zhong Z, Karin M, Beyaert R. Limiting inflammation-the negative regulation of NF-kappaB and the NLRP3 inflammasome. Nat Immunol. 2017;18:861–9.
Salt IP, Palmer TM. Exploiting the anti-inflammatory effects of AMP-activated protein kinase activation. Expert Opin Investig Drugs. 2012;21:1155–67.
O’Neill LA, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature. 2013;493:346–55.
Cheng C, Wang T, Song Z, Peng L, Gao M, Hermine O, et al. Induction of autophagy and autophagy-dependent apoptosis in diffuse large B-cell lymphoma by a new antimalarial artemisinin derivative, SM1044. Cancer Med. 2018;7:380–96.
Zhao X, Fang J, Li S, Gaur U, Xing X, Wang H, et al. Artemisinin attenuated hydrogen peroxide (H2O2)-induced oxidative injury in SH-SY5Y and hippocampal neurons via the activation of AMPK pathway. Int J Mol Sci. 2019;20:2680.
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.
The authors declare no competing interests.
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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
- cognitive dysfunction
- AMP-activated protein kinases