Ethyl pyruvate protects against sepsis-associated encephalopathy through inhibiting the NLRP3 inflammasome
Open accessAbstract
Background: With the advance of antibiotics and life support therapy, the mortality of sepsis has been decreasing in recent years. However, the incidence of sepsis-associated encephalopathy (SAE), a common complication of sepsis, is still high. There are few effective therapies to treat clinical SAE. We previously found that ethyl pyruvate (EP), a metabolite derivative, is able to effectively inhibit the NLRP3 inflammasome activation. Administration of ethyl pyruvate protects mice against polymicrobial sepsis in cecal ligation and puncture (CLP) model. The aim of present study is to investigate if ethyl pyruvate is able to attenuate SAE. Methods: After CLP, C57BL/6 mice were intraperitoneally or intrathecally injected with saline or ethyl pyruvate using the sham-operated mice as control. New Object Recognition (NOR) and Morris Water Maze (MWM) were conducted to determine the cognitive function. Brain pathology was assessed via immunohistochemistry. To investigate the mechanisms by which ethyl pyruvate prevent SAE, the activation of NLRP3 in the hippocampus and the microglia were determined using western blotting, and cognitive function, microglia activation, and neurogenesis were assessed using WT, Nlrp3−/− and Asc−/− mice in the sublethal CLP model. In addition, Nlrp3−/− and Asc−/− mice treated with saline or ethyl pyruvate were subjected to CLP. Results: Ethyl pyruvate treatment significantly attenuated CLP-induced cognitive decline, microglia activation, and impaired neurogenesis. In addition, EP significantly decreased the NLRP3 level in the hippocampus of the CLP mice, and inhibited the cleavage of IL-1β induced by NLRP3 inflammsome in microglia. NLRP3 and ASC deficiency demonstrated similar protective effects against SAE. Nlrp3−/− and Asc−/− mice significantly improved cognitive function and brain pathology when compared with WT mice in the CLP models. Moreover, ethyl pyruvate did not have additional effects against SAE in Nlrp3−/− and Asc−/− mice. Conclusion: The results demonstrated that ethyl pyruvate confers protection against SAE through inhibiting the NLRP3 inflammasome.
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Reducing IL-1β levels through inhibition of NLRP3 in microglia improves cognitive function in sepsis.
“Reducing IL-1β levels through inhibition of NLRP3 in microglia was shown to improve cognitive function in sepsis (19, 36).”
From Sepsis-Induced Gut Dysbiosis Mediates the Susceptibility to Sepsis-Associated Encephalopathy in Mice (2022) · cites this paper as [36]
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BENEFICIAL EFFECTS OF ETHYL PYRUVATE IN A MOUSE MODEL OF SPINAL CORD INJURY
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“Intervention strategies classified by clinical transformation stage: 1 ⃝ Preclinical research: Ethyl pyruvate inhibits NLRP3 [80]; TXNIP knockdown protects against sepsis-induced brain injury and cognitive decline by suppressing oxidative stress and neuroin-flammation [81]; mesenchymal stem…”
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- Authors
- Zhong, X., Xie, L., Yang, X., Liang, F., Yang, Y., Tong, J., Zhong, Y., Zhao, K., Tang, Y., & Yuan, C.
- Affiliations
- Central South University (CN)
- Third Xiangya Hospital (CN)
- Corresponding author
- Tang, Yiting
- Yuan, Chuang
- ORCID
- Venue
- Molecular Medicine
- Published
- 2020-06-09
- Volume
- 26
- Issue
- 1
- Pages
- 55-55
- ISSN
- 1076-1551 (ISSN-L)
- 1528-3658
- PMC
- PMC7285451
- OpenAlex
- W3033994946
- Cited by
- 42
- References
- 98
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 6 · 2023: 12 · 2022: 7 · 2021: 6 · 2020: 2
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81700127, 81602735, 81701962, 81801967)
- Project of Hunan health (C2016066)
- Natural science foundation of Hunan Province (2018JJ32589)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
- Keywords
- ethyl pyruvate, sepsis-associated encephalopathy, NLRP3 inflammasome, polymicrobial sepsis, cecal ligation and puncture, cognitive decline, microglial activation, neurogenesis, hippocampus, IL-1β, ASC, NLRP3, neuroprotection
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Disease Models, Animal, Hippocampus, Injections, Spinal, Male, Neurons, Pyruvates, Microglia, Protective Agents, Mice, Inflammasomes, Cognitive Dysfunction, Sepsis-Associated Encephalopathy
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