Up-regulation of brain cytokines and chemokines mediates neurotoxicity in early acute liver failure by a mechanism independent of microglial activation

• Published in: Brain research 2014-08, Vol.1578, p.49-59
• Main Authors: Faleiros, Bruno E, Miranda, Aline S, Campos, Alline C, Gomides, Lindisley F, Kangussu, Lucas M, Guatimosim, Cristina, Camargos, Elizabeth R.S, Menezes, Gustavo B, Rachid, Milene A, Teixeira, Antônio L
• Format: Article
• Language: English
• Subjects: Acute liver failure; Animals; Biological and medical sciences; Brain - metabolism; Brain - ultrastructure; Cell Count; Chemokine; Chemokines - blood; Chemokines - metabolism; Cytokine; Cytokines - blood; Cytokines - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Leukocyte Rolling; Liver - pathology; Liver Failure, Acute - chemically induced; Liver Failure, Acute - metabolism; Liver Failure, Acute - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mice; Mice, Inbred C57BL; Microglia; Microglia - cytology; Microglia - metabolism; Motor Activity - drug effects; Neuroinflammation; Neurology; Other diseases. Semiology; Thioacetamide; Thioacetamide - toxicity; Up-Regulation; Vertebrates: nervous system and sense organs
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2014.07.001

Abstract The neurological involvement in acute liver failure (ALF) is characterized by arousal impairment with progression to coma. There is a growing body of evidence that neuroinflammatory mechanisms play a role in this process, including production of inflammatory cytokines and microglial activation. However, it is still uncertain whether brain-derived cytokines and glial cells are crucial to the pathophysiology of ALF at the early stage, before coma development. Here, we investigated the influence of cytokines and microglia in ALF-induced encephalopathy in mice as soon as neurological symptoms were identifiable. Behavior was assessed at 12, 24, 36 and 48 h post-injection of thioacetamide, a hepatotoxic drug, through locomotor activity by an open field test. Brain concentration of cytokines (TNF-α and IL-1β) and chemokines (CXCL1, CCL2, CCL3 and CCL5) were assessed by ELISA. Microglial activation in brain sections was investigated through immunohistochemistry, and cellular ultrastructural changes were observed by transmission electron microscopy. We found that ALF-induced animals presented a significant decrease in locomotor activity at 24 h, which was accompanied by an increase in IL-1β, CXCL1, CCL2, CCL3 and CCL5 in the brain. TNF-α level was significantly increased only at 36 h. Despite marked morphological changes in astrocytes and brain endothelial cells, no microglial activation was observed. These findings suggest an involvement of brain-derived chemokines and IL-1β in early pathophysiology of ALF by a mechanism independent of microglial activation.