Abstract
BackgroundWith 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.MethodsAfter 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.ResultsEthyl 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.ConclusionThe results demonstrated that ethyl pyruvate confers protection against SAE through inhibiting the NLRP3 inflammasome.
Highlights
Sepsis is a systemic inflammatory response syndrome (SIRS) caused by infection (Buras et al 2005; Singer et al 2016)
Ethyl pyruvate attenuates cognitive decline in experimental sepsis To determine whether ethyl pyruvate could improve learning and memory dysfunction in septic mice, we used New Object Recognition (NOR) and Morris Water Maze (MWM) test after the mice subjected to moderate cecal ligation and puncture (CLP) or sham operation
After the mouse restored its mobility (Day 12, Fig. 1b), we carried out NOR test (Day 13) which was followed by MWM test (Day 15)
Summary
Sepsis is a systemic inflammatory response syndrome (SIRS) caused by infection (Buras et al 2005; Singer et al 2016). In addition to high mortality at the early stage, sepsis can cause sepsis-associated encephalopathy (SAE), which significantly increases the mortality of patients and largely influences the life quality of sepsis survivors (Eidelman et al 1996; Ebersoldt et al 2007; Widmann et al 2014; Annane and Sharshar 2015). SAE is characterized by diffuse brain dysfunction after the onset of sepsis, without infection in the central nervous system (Eidelman et al 1996; Ebersoldt et al 2007; Chen et al 2014; Widmann et al 2014; Annane and Sharshar 2015). With the advance of antibiotics and life support therapy, the mortality of sepsis has been decreasing in recent years. The aim of present study is to investigate if ethyl pyruvate is able to attenuate SAE
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
