Ethyl pyruvate protects against sepsis-associated encephalopathy through inhibiting the NLRP3 inflammasome

Abstract

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.