NLRP3 Activation Contributes to Acute Brain Damage Leading to Memory Impairment in Sepsis-Surviving Rats
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NLRP3 Activation Contributes to Acute Brain Damage Leading to Memory Impairment in Sepsis-Surviving Rats Lucineia Gainski Danielski 1 & Amanda Della Giustina 1 & Sandra Bonfante 1 & Mariana Pereira de Souza Goldim 1 & Larissa Joaquim 1 & Kiuanne Lobo Metzker 1 & Erica Bernardo Biehl 1 & Thaynan Vieira 1 & Fabiana Durante de Medeiros 1 & Naiana da Rosa 1 & Jaqueline Generoso 2 & Lutiana Simoes 2 & Hémelin Resende Farias 3 & Isabela da Silva Lemos 3 & Vijayasree Giridharan 4 & Gislaine Tezza Rezin 1 & Jucelia Jeremias Fortunato 1 & Rafael Mariano Bitencourt 1 & Emilio Luiz Streck 3 & Felipe Dal-Pizzol 2 & Tatiana Barichello 2,4 & Fabricia Petronilho 1 Received: 2 April 2020 / Accepted: 24 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Sepsis survivors present acute and long-term cognitive impairment and the pathophysiology of neurological dysfunction in sepsis involves microglial activation. Recently, the involvement of cytosolic receptors capable of forming protein complexes called inflammasomes have been demonstrated to perpetuate neuroinflammation. Thus, we investigated the involvement of the NLRP3 inflammasome activation on early and late brain changes in experimental sepsis. Two-month-old male Wistar rats were submitted to the sepsis model by cecal ligation and perforation (CLP group) or laparotomy only (sham group). Immediately after surgery, the animals received saline or NLRP3 inflammasome formation inhibitor (MCC950, 140 ng/kg) intracerebroventricularly. Prefrontal cortex and hippocampus were isolated for cytokine analysis, microglial and astrocyte activation, oxidative stress measurements, nitric oxide formation, and mitochondrial respiratory chain activity at 24 h after CLP. A subset of animals was followed for 10 days for survival assessment, and then behavioral tests were performed. The administration of MCC950 restored the elevation of IL-1β, TNF-α, IL-6, and IL-10 cytokine levels in the hippocampus. NLRP3 receptor levels increased in the prefrontal cortex and hippocampus at 24 h after sepsis, associated with microglial, but not astrocyte, activation. MCC950 reduced oxidative damage to lipids and proteins as well as preserved the activity of the enzyme SOD in the hippocampus. Mitochondrial respiratory chain activity presented variations in both structures studied. MCC950 reduced microglial activation, decreased acute neurochemical and behavioral alteration, and increased survival after experimental sepsis. Keywords Sepsis . NLRP3 . Inflammasome . MCC950 . Neuroinflammation . Cognitive impairment
Introduction * Fabricia Petronilho [email protected] 1
Laboratory of Neurobiology of Inflammatory and Metabolic Processes, Graduate Program in Health Sciences, Health Sciences Unit, University of South Santa Catarina, Tubarão, SC, Brazil
2
Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, Brazil
3
Laboratory of Experimental Neurology, Graduate Pro
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