Hepatic encephalopathy induces anxiety and depression-like behaviors, cytokine dysfunction, BDNF down-regulation and neuropathological changes in mice

Psychiatric disorders, such as disturbance of sleep, irritability, anxiety and depressive symptoms have been reported in patients with hepatic encephalopathy (HE). However, these neuropsychiatric disorders in patients with HE remains largely unknown. The present study aimed to explore if acute HE lead to anxiety and depression-like behaviors and alterations in the levels of inflammatory cytokines, chemokines and neurotrophic levels in the pre-frontal cortex, striatum and hippocampus as well as neuropathological changes in mice. HE was induced by an intraperitoneal single dose of 600 mg/kg of thioacetamide (TAA). Behavioral symptoms were assessed by open field, elevated plus maze and forced swimming tests. Measurements of cytokines [tumor necrosis factor (TNF), interferon-gamma (IFN-γ), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 12p70 (IL-12 p70), interleukin-1-beta (IL-1β)], chemokines [chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-X-C motif) ligand 1 (CXCL1), C-X3-C motif chemokine ligand 1 (CX3CL1)] and neurotrophic factors [brain-derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), nerve growth factor (NGF)] from pre-frontal cortex, striatum and hippocampus were obtained by CBA and ELISA assays. Liver dysfunction and injury were evaluated by serum liver enzymes and histopathological analysis. We evaluated immunohistochemistry for GFAP and Iba-1 at different brain regions. TAA induced liver necrosis, inflammation and increased serum levels of liver enzymes and myeloperoxidase (MPO), N-acetylglucosaminidase (NAG) activities. Seven days post induction, mice with HE developed anxiety and depression-like behaviors and exhibited areas of astrogliosis and reactive microglia in the cerebral cortex and hippocampus. Additionally, HE animals showed lower levels of BDNF and higher concentrations of IL-1β in the pre-frontal cortex and lower levels of IFN-γ and IL-6 in the hippocampus. Our data revealed for the first time that acute hepatic encephalopathy causes anxiety and depression-like behaviors, cytokine dysfunction, BDNF down-regulation and neuropathological changes in mice.