Saran Tomasz, Hilgier Wojciech, Urbańska Ewa M, Turski Waldemar A, Albrecht Jan
Department of Pharmacology and Toxicology, Medical University, Lublin, Poland.
J Neurosci Res. 2004 Feb 1;75(3):436-40. doi: 10.1002/jnr.10862.
Increased ammonia is a major pathogenic factor in hepatic encephalopathy (HE), a neurologic syndrome associated with glutamatergic dysfunction. Previous studies have shown that in rat cerebral cortical slices or a glia-derived cell line, acute treatment with ammonia in vitro and in vivo inhibits the production of a broad-spectrum antagonist of excitatory amino acid receptors, kynurenic acid (KYNA). The present study analyzed KYNA synthesis in cerebral cortical slices obtained from rats with progressing HE symptoms accompanying acute liver failure induced by one, two, or three intraperitoneal administrations of thioacetamide (TAA) at 24-hr intervals. KYNA synthesis was found decreased to 83% of control 24 hr after one administration of TAA and unaffected after two TAA injections, when moderate hyperammonemia was associated by metabolic and bioelectric activation of the central nervous system, but was not accompanied by typical HE symptoms. KYNA synthesis was elevated to 155% of control after three TAA administrations, a period in which the rats showed advanced HE symptoms including stupor or coma. KYNA synthesis at the advanced HE stage was inhibited by glutamate in a degree comparable to that observed in control slices. The elevation of KYNA synthesis was associated with increased activity of a kynurenine aminotransferase (KAT) isomer, KAT-II. KYNA synthesis did not differ from control 21 days after the third TAA administration when HE symptoms receded. The results suggest that alterations of KYNA synthesis may contribute to the imbalance between neural excitation and inhibition at different stages of HE.
血氨升高是肝性脑病（HE）的主要致病因素，肝性脑病是一种与谷氨酸能功能障碍相关的神经综合征。先前的研究表明，在大鼠大脑皮层切片或胶质细胞衍生细胞系中，体外和体内用氨急性处理会抑制兴奋性氨基酸受体的广谱拮抗剂犬尿喹啉酸（KYNA）的产生。本研究分析了从硫代乙酰胺（TAA）腹腔注射诱导急性肝衰竭且伴有进行性HE症状的大鼠获取的大脑皮层切片中KYNA的合成情况，TAA每隔24小时腹腔注射一次，共注射1次、2次或3次。结果发现，单次注射TAA后24小时，KYNA合成降至对照组的83%，两次注射TAA后未受影响，此时伴有中枢神经系统代谢和生物电激活引起的中度高氨血症，但未出现典型的HE症状。三次注射TAA后，KYNA合成升高至对照组的155%，此时大鼠出现包括昏迷或昏睡在内的晚期HE症状。晚期HE阶段的KYNA合成受到谷氨酸的抑制，其程度与对照组切片中观察到的相当。KYNA合成的升高与犬尿氨酸转氨酶（KAT）异构体KAT-II的活性增加有关。第三次注射TAA 21天后，当HE症状消退时，KYNA合成与对照组无差异。结果表明，KYNA合成的改变可能导致HE不同阶段神经兴奋与抑制之间的失衡。
