Investigação do envolvimento do inflamassoma nlrp3 sobre alterações cerebrais precoces e tardias após a sepse

• Autor(a) principal: Danielski, Lucineia Gainski
• Data de Publicação: 2020
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Repositório Universitário da Ânima (RUNA)
• Texto Completo: https://repositorio.animaeducacao.com.br/handle/ANIMA/15190
• topic: Sespe; Microglia; NLRP3

Introduction: Surviving sepsis patients develop acute and long-term cognitive damage and microglial activation is involved in its pathophysiology. Recently, they have been identified as protein-forming receptors, called inflammasomes. The NLRP3 inflammasome may be present with the exacerbation of the microglial inflammatory response after sepsis. Objective: To investigate the involvement of the NLRP3 inflammasome in early and late brain changes in experimental sepsis. Methods: Two-month-old male Wistar rats submitted to sepsis by cecal ligation and perforation (CLP group) or only laparotomy (sham group). Immediately, they received saline or NLRP3 inflammasome inhibitor (MCC950, 140 ng / kg), via icv. Twenty-four hours later, prefrontal cortex and hippocampus were isolated for analysis of cytokine levels, NLRP3 levels, microglial and astrocyte activation, measures of oxidative stress, nitrite/nitrate formation and mitochondrial respiratory chain activity. Survival was assessed for ten days, and then behavioral tests were performed. Results: MCC950 prevented elevated levels of cytokines IL-1β, TNF-α, IL-6 and IL-10 in the hippocampus, 24 hours after sepsis. At the same time, there was an increase in the levels of the NLRP3 receptor in the prefrontal cortex and hippocampus, associated with microglial activation, but not astrocyte. MCC950 prevented damage to lipids and proteins, as well as preserved the activity of the SOD enzyme in the hippocampus. There was variation in the activity of the mitochondrial respiratory chain, with no recognizable pattern. The administration of a single dose of the inhibitor of NLRP3 formation, improved survival, and decreased cognitive damage in animals evaluated 10 days after sepsis. Conclusion: The NLRP3 inflammasome formation is associated with acute biochemical and neuroinflammatory changes, increased mortality and the presence of long-term cognitive damage after experimental sepsis.