Brief Article
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World J Hepatol. Apr 27, 2014; 6(4): 243-250
Published online Apr 27, 2014. doi: 10.4254/wjh.v6.i4.243
Murine model to study brain, behavior and immunity during hepatic encephalopathy
Lindisley Ferreira Gomides, Pedro Elias Marques, Bruno Engler Faleiros, Rafaela Vaz Pereira, Sylvia Stella Amaral, Thais Reis Lage, Gustavo Henrique Souza Resende, Patricia Alves Maia Guidine, Giselle Foureaux, Fabíola Mara Ribeiro, Fabiana Paiva Martins, Marco Antônio Peliky Fontes, Anderson José Ferreira, Remo Castro Russo, Mauro Martins Teixeira, Márcio Flávio Moraes, Antonio Lúcio Teixeira, Gustavo Batista Menezes
Lindisley Ferreira Gomides, Pedro Elias Marques, Rafaela Vaz Pereira, Sylvia Stella Amaral, Thais Reis Lage, Gustavo Batista Menezes, Laboratório de Imunobiofotônica, Department of Morphology, ICB, UFMG, Belo Horizonte 31270-901, Brazil
Bruno Engler Faleiros, Fabiana Paiva Martins, Antonio Lúcio Teixeira, School of Medicine, UFMG, Belo Horizonte 31270-901, Brazil
Gustavo Henrique Souza Resende, Patricia Alves Maia Guidine, Marco Antônio Peliky Fontes, Remo Castro Russo, Márcio Flávio Moraes, Department of Physiology, ICB, UFMG, Belo Horizonte 31270-901, Brazil
Giselle Foureaux, Anderson José Ferreira, Department of Morphology, UFMG, Belo Horizonte 31270-901, Brazil
Fabíola Mara Ribeiro, Mauro Martins Teixeira, Department of Biochemistry and Immunology, UFMG, Belo Horizonte 31270-901, Brazil
Author contributions: Gomides LF, Marques PE, Faleiros BE, Pereira RV, Amaral SS, Lage TR, Resende GHS, Guidine PAM, Foureaux G, Ribeiro FM and Martins FP performed the majority of experiments and analyzed data; Fontes MAP, Ferreira AJ, Russo RC, Teixeira MM, Moraes MF and Teixeira AL performed experiments and interpreted results; Menezes GB designed the study and wrote the manuscript; Gomides LF, Marques PE and Menezes GB revised the manuscript; all authors approved the final version to be published.
Correspondence to: Gustavo Batista Menezes, PhD, Laboratório de Imunobiofotônica, Department of Morphology, ICB, UFMG, Av. Antonio Carlos, 6627 - Pampulha, Belo Horizonte 31270-901, Brazil.
Telephone: +55-31-34093015  Fax: +55-31-34093015
Received: November 21, 2013
Revised: January 17, 2014
Accepted: February 16, 2014
Published online: April 27, 2014

AIM: To propose an alternative model of hepatic encephalopathy (HE) in mice, resembling the human features of the disease.

METHODS: Mice received two consecutive intraperitoneal injections of thioacetamide (TAA) at low dosage (300 mg/kg). Liver injury was assessed by serum transaminase levels (ALT) and liver histology (hematoxylin and eosin). Neutrophil infiltration was estimated by confocal liver intravital microscopy. Coagulopathy was evaluated using prolonged prothrombin and partial thromboplastin time. Hemodynamic parameters were measured through tail cuff. Ammonia levels were quantified in serum and brain samples. Electroencephalography (EEG) and psychomotor activity score were performed to show brain function. Brain edema was evaluated using magnetic resonance imaging.

RESULTS: Mice submitted to the TAA regime developed massive liver injury, as shown by elevation of serum ALT levels and a high degree of liver necrosis. An intense hepatic neutrophil accumulation occurred in response to TAA-induced liver injury. This led to mice mortality and weight loss, which was associated with severe coagulopathy. Furthermore, TAA-treated mice presented with increased serum and cerebral levels of ammonia, in parallel with alterations in EEG spectrum and discrete brain edema, as shown by magnetic resonance imaging. In agreement with this, neuropsychomotor abnormalities ensued 36 h after TAA, fulfilling several HE features observed in humans. In this context of liver injury and neurological dysfunction, we observed lung inflammation and alterations in blood pressure and heart rate that were indicative of multiple organ dysfunction syndrome.

CONCLUSION: In summary, we describe a new murine model of hepatic encephalopathy comprising multiple features of the disease in humans, which may provide new insights for treatment.

Keywords: Hepatic encephalopathy, Liver injury, Thioacetamide, Neurological dysfunction, Neuropsychomotor abnormalities, Intracranial hypertension, Cerebral herniation

Core tip: The study of hepatic encephalopathy is crucial for development of new therapies but has been dampened by the absence of murine models resembling the disease in patients. We showed that sequential thioacetamide injections cause extensive liver injury in mice, leading to increased ammonia levels, electroencephalography alterations and brain edema. In line with this, mice presented with poor psychomotor activity and survival rate. Liver injury and brain function impairment by thioacetamide resulted in systemic alterations such as coagulopathy, hemodynamic instability and lung inflammation, consistent with multiple organ failure. Therefore, this alternative model may provide tools for new therapeutic insights for hepatic encephalopathy.