A new hepatic encephalopathy model to monitor the change of neural amino acids and astrocytes with behaviour disorder

• Published in: Liver international Vol. 28; no. 1; pp. 117 - 125
• Main Authors: Isobe-Harima, Yumiko, Terai, Shuji, Miura, Izumi, Segawa, Makoto, Murata, Tomoaki, Itamoto, Kazuhito, Taura, Yasuho, Shinoda, Koh, Sakaida, Isao
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2008
• Subjects: Acetaminophen - toxicity; Amino Acids - metabolism; Animals; aspartate; astrocytes; Astrocytes - metabolism; behaviour disorder; Blotting, Western; Brain - metabolism; Disease Models, Animal; Electric Stimulation; glutamate; hepatic encephalopathy; Hepatic Encephalopathy - chemically induced; Hepatic Encephalopathy - metabolism; Hepatic Encephalopathy - pathology; Immunohistochemistry; Male; Methylcholanthrene - toxicity; Psychomotor Performance - drug effects; Rats; Rats, Wistar; vertical activity
• ISSN: 1478-3223; 1478-3231
• DOI: 10.1111/j.1478-3231.2007.01589.x

Background/Aims: To elucidate the pathogenesis of hepatic encephalopathy (HE), we developed a new HE model with behaviour disorder. Methods: Male Wistar rats were divided into four treatment groups: a HE model: acetaminophen (APAP)+3‐methylcholanthrene (3‐MC) group (APAP+MC group); control group: acetaminophen group; 3‐methylcholanthrene group; and a no‐treatment group. We monitored the changes of neural amino acids in the synaptic cleft and astrocytes in the brain during behaviour disorder. Results: In the APAP+MC group, alanine amino transferase, blood ammonia and glucose increased from 3 h and total bilirubin increased at 6 h. Prothrombin time was prolonged from 3 h in the APAP+MC group. The APAP+MC group exhibited centrilobular necrosis in the liver after 8 h. In the APAP+MC group, rats jumped vertically and this vertical activity increased significantly from 4 to 7 h. During the behaviour disorder, we found that glutamate and aspartate increased in the synaptic cleft from 4 h after treatment with APAP+3‐MC, glutamate increased 23.9‐fold at 7 h and aspartate increased 16.1‐fold at 4 h, whereas glutamine did not change. At that time, we observed morphological changes of the astrocytes by immunostaining for the glial fibrillary acidic protein. Conclusions: Our new HE model demonstrated that increased excitatory neural amino acids and morphological change in astrocytes were involved in the behaviour disorder that occurs with HE.