Avaliação dos componentes do sistema renina-angiotensina e dos parâmetros inflamatórios e neuroquímicos no córtex pré-frontal e no hipocampo de camundongos com encefalopatia hepática induzida por tioacetamida

Abstract

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that involves cognitive and motor dysfunctions due to liver failure. The liver plays an important role in lipid and macronutrient metabolism, in detoxification, and blood volume regulation. Thioacetamide is commonly used to induce acute liver injury, liver fibrosis and cirrhosis in mice and other experimental models. Thioacetamide can induce disseminated intracellular vacuolization, hepatocellular necrosis, and infiltration of inflammatory cells in the liver. Clinical and experimental studies suggest that the angiotensin converting enzyme (ACE), Angiotensin (Ang) II, and angiotensin type 1 receptor (AT1R), that compose the classical pathway of the renin–angiotensin system (RAS), exacerbate neuroinflammation in different neurologic diseases. Conversely, Ang-(1-7), ACE2, and Mas receptor, which integrate the alternative RAS axis, have been shown as a promise therapeutic target in neuropsychiatric disorders, leading to neuroprotection. This study aimed to investigate the participation of the RAS components and the levels of neurotrophic factors, pro-inflammatory cytokines, and chemokine in pre-frontal cortex and hippocampus of TAA-induced HE in mice. We also evaluated the histopathological and biochemical changes in the liver of affected mice. Mice presented increased cortical levels of ACE and decreased levels of Ang-(1-7) in pre-frontal cortex and hippocampal samples compared to controls. HE mice had an increase in the Ang II/Ang-(1-7) ratio along with reduced levels of neural growth factor (NGF) in the prefrontal cortex. The animals also showed elevated levels of IFN-γ and CCL2 in the prefrontal cortex and of TNF, IL-6, IL-12, and CCL2 in the hippocampus, compared with controls. TAA promoted hemorrhagic necrosis and inflammation associated with increased levels of hepatic markers, and higher activity of neutrophils and macrophages. Our data suggest the possible participation of components of the RAS in the pathophysiology of TAA-induced HE. It is suggested that the reduction of components of the alternative RAS axis is associated with the deleterious effects of neuroinflammation and lower neuroprotective effects of NGF in the disease.