Investigação dos processos neuroinflamatórios em um modelo murino de encefalopatia hepática por falência hepática aguda

Abstract

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that results from acute liver failure (ALF) and one of its major complications. HE emergence implies an increase in the severity and risk of death in these patients. In its pathophysiological process, HE develops in consequence of hyperammonemia in the brain and a neuroinflammatory response with increased proinflammatory cytokines and oxidative and nitrosative stress. The understanding of neuroinflammation in this scenario is important to expand the clinical spectrum of therapeutic intervention in HE and improve survival in ALF. Therefore, the objective of this study was to elucidate the cellular profile involvement and inflammatory response in the brain of mice with HE induced by thioacetamide, a hepatotoxic drug. The locomotor activity was used as a parameter to evaluate clinical presentation and severity of symptoms in the experimental models of this study. We observed that in 24, 36 and 48 hours post-induction of HE, there was significant reduction in the movement of these animals. Furthermore, in 24 hours, this reduction was more relevant compared to the control group. In parallel with this early and intense symptomatic scenario, we also noticed an increase in the level of brain proinflammatory cytokine IL-1 and chemokines CXCL1/KC,CCL2/MCP-1, CCL3/MIP-1 and CCL5/RANTES. Moreover, there was also a higher gradient of cytokine TNF- in the brain when compared to blood, and a diminished activity of antioxidant enzymes SOD, GSH-Px and catalase. By investigating the cellular participation in this process, we observed no leukocyte infiltration or activation of microglia, resident myeloid cells in the central nervous system, although there was evidence of involvement of astrocytes, the target cell in the process. Thus, we describe in a moment early in the development of HE, a neuroinflammatory process that is probably related to astrocyte, wherein the oxidative stress and the production of cytokines and chemokines in the brain may contribute to the intensity of symptoms. Further studies are needed to elucidate the mechanisms of participation of astrocytes andother cells of HE in addition to investigate the weighted importance of inflammation and oxidative stress in its development.