A thioacetamide-induced hepatic encephalopathy model in C57BL/6 mice: a behavioral and neurochemical study

Abstract

Objective: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome resulting from liver failure. In the present study, we aimed to standardize an animal model of HE induced by thioacetamide (TAA) in C57BL/6 mice evaluating behavioral symptoms in association with liver damage and alterations in neurotransmitter release. Method: HE was induced by an intraperitoneal single dose of TAA (200 mg/kg, 600 mg/kg or 1,200 mg/kg). Behavioral symptoms were evaluated using the SHIRPA battery. Liver damage was confirmed by histopathological analysis. The glutamate release was measured using fluorimetric assay. results: The neuropsychiatric state, motor behavior and reflex and sensory functions were significantly altered in the group receiving 600 mg/kg of TAA. Biochemical analysis revealed an increase in the glutamate release in the cerebral cortex of HE mice. conclusion: HE induced by 600mg/kg TAA injection in C57BL/6 mice seems to be a suitable model to investigate the pathogenesis and clinical disorders of HE. Key words: hepatic encephalopathy, thioacetamide, behavioral changes, SHIRPA, glutamate.Modelo de encefalopatia hepática induzida por tioacetamida em camundongos c57bL/6: estudo comportamental e neuroquímico resuMO Objetivo: A encefalopatia hepática (EH) é uma síndrome neuropsiquiátrica resultante da falência hepática. O objetivo do presente estudo foi estabelecer um modelo de EH induzida por tioacetamida (TAA) em camundongos C57BL/6 avaliando transtornos comportamentais, falência hepática e alterações na liberação de neurotransmissores. Método: A EH foi induzida por meio de uma única dose intraperitoneal de TAA (200 mg/kg, 600 mg/kg, 1.200 mg/kg). As alterações comportamentais foram avaliadas utilizando a bateria SHIRPA. A falência hepática foi confirmada através de análises histopatológicas e a liberação de glutamato medida, por ensaio fluorimétrico. resultados: Foram encontradas alterações significativas no estado neuropsiquiátrico, comportamento motor e função reflexa e sensorial no grupo que recebeu 600 mg/kg de TAA. Análises bioquímicas revelaram aumento na liberação de glutamato no córtex cerebral dos camundongos com EH. conclusão: A EH induzida por 600 mg/kg de TAA em camundongos C57BL/6 parece ser um modelo apropriado para a investigação da patogênese e dos transtornos clínicos da EH.

Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy

“…Brain accumulation of ALLO and THDOC potentiates GABAergic transmission by positive allosteric modulation of GABA A receptor function and contributes to the imbalance between excitation and inhibition in HE (2, 54, 55). ALLO and THDOC are known to induce significant alterations of the sleep/wake cycle (44), as well as to decrease cognitive performance in rodents (33), changes that are also present in human HE.Although there is no ideal model of HE, it is well known that thioacetamide (TAA), a sulfur-containing compound, may induce acute liver failure with potentially reversible brain damage (38,39,41,46). TAA was widely used for investigation of the role of glutamine (50), oxidative stress (40), and disturbances in glutamatergic and GABAergic neurotransmission (38,45) in the pathogenesis of type A HE.…”

“…Although there is no ideal model of HE, it is well known that thioacetamide (TAA), a sulfur-containing compound, may induce acute liver failure with potentially reversible brain damage (38,39,41,46). TAA was widely used for investigation of the role of glutamine (50), oxidative stress (40), and disturbances in glutamatergic and GABAergic neurotransmission (38,45) in the pathogenesis of type A HE.…”

“…TAA was widely used for investigation of the role of glutamine (50), oxidative stress (40), and disturbances in glutamatergic and GABAergic neurotransmission (38,45) in the pathogenesis of type A HE.…”

Murine model to study brain, behavior and immunity during hepatic encephalopathy

“…Also, persistent hyperammonemia seems to be more important than a transient increase in the ammonia level regarding the occurrence of intracranial hypertension [19] . Most studies in mice used a single dose of a hepatotoxic drug which caused a briefer period of illness [20][21][22] . To supersede this, we developed a novel protocol using a lower TAA dose (300 mg/kg) and repeated administration (2 daily doses), trying to mimic a more realistic scenario closer to severe HE.…”

Quantification of thioacetamide-induced liver necrosis using fractal analysis

“…High levels of ammonia are associated with hepatic encephalopathy (HE), a severe neuropsychiatric syndrome (6). Thioacetamide (TAA) is a substance commonly used to induce a model of acute liver failure, as well as HE in rats (7)(8)(9). TAA causes hepatocellular necrosis after biotransformation to an active metabolite and by generating ROS (3).…”