Peeling J, Shoemaker L, Gauthier T, Benarroch A, Sutherland G R, Minuk G Y
Department of Radiology, University of Manitoba, Winnipeg, Canada.
Am J Physiol. 1993 Sep;265(3 Pt 1):G572-8. doi: 10.1152/ajpgi.1993.265.3.G572.
Acute liver failure was induced in rats by successive administrations of thioacetamide over 3 days. At progressing stages of hepatic encephalopathy (HE), brains were fixed with microwave irradiation for analysis of metabolite levels or with formaldehyde for histopathological analysis. Metabolite levels were determined using 1H-nuclear magnetic resonance spectroscopy of perchloric acid extracts of the frontal cortex, parietal or occipital cortex, hippocampus, striatum, brain stem, and cerebellum. After thioacetamide treatment, thioacetamide and its metabolites were detected in the brains at levels that did not correlate with the stage of HE. No changes were observed in the levels of N-acetylaspartate, alanine, gamma-aminobutyric acid, aspartate, or inositol in any brain region after thioacetamide treatment. HE was accompanied by elevated glutamine, glucose, and lactate throughout the brain. At all stages of HE, taurine was decreased in the neocortex and hippocampus, and glutamate and choline compounds were decreased in the frontal cortex. None of the metabolite changes showed progression with the stage of HE. Progressing HE was accompanied by increasing neuronal injury in layer III of the neocortex, in the Purkinje cells of the cerebellum, and in the hippocampus, particularly in the CA4 sector. The similarity of this distribution of injury to that associated with excitotoxic injury suggests that metabolic abnormalities after acute hepatic failure may give rise to adverse effects at excitatory (glutamatergic) neuronal receptors, leading to neuronal injury and clinical symptoms of progressing encephalopathy in this model. However, neuronal injury and the presence of thioacetamide and its metabolites in the brain raise questions about the validity of thioacetamide-induced liver failure as a model for clinical HE.
通过连续3天给予硫代乙酰胺在大鼠中诱导急性肝衰竭。在肝性脑病（HE）进展阶段，将大脑用微波辐射固定以分析代谢物水平，或用甲醛固定以进行组织病理学分析。使用额叶皮质、顶叶或枕叶皮质、海马体、纹状体、脑干和小脑的高氯酸提取物的1H-核磁共振波谱法测定代谢物水平。硫代乙酰胺治疗后，在大脑中检测到硫代乙酰胺及其代谢物，其水平与HE阶段无关。硫代乙酰胺治疗后，任何脑区的N-乙酰天门冬氨酸、丙氨酸、γ-氨基丁酸、天冬氨酸或肌醇水平均未观察到变化。HE伴有全脑谷氨酰胺、葡萄糖和乳酸升高。在HE的所有阶段，新皮质和海马体中的牛磺酸减少，额叶皮质中的谷氨酸和胆碱化合物减少。没有一种代谢物变化显示随着HE阶段进展。进展性HE伴有新皮质III层、小脑浦肯野细胞和海马体（特别是CA4区）神经元损伤增加。这种损伤分布与兴奋性毒性损伤相关的损伤分布相似，表明急性肝衰竭后的代谢异常可能在兴奋性（谷氨酸能）神经元受体处产生不良反应，导致该模型中神经元损伤和进展性脑病的临床症状。然而，神经元损伤以及硫代乙酰胺及其代谢物在大脑中的存在，引发了关于硫代乙酰胺诱导的肝衰竭作为临床HE模型有效性的质疑。
