dizocilpine-maleate and Chemical-and-Drug-Induced-Liver-Injury

Kynurenine aminotransferase II (KAT-II) is the astrocytic enzyme catalyzing the synthesis of kynurenic acid (KYNA), an endogenous inhibitor of the α7-nicotinic receptor and the NMDA receptor (NMDAr). A previous study demonstrated an increase of KYNA synthesis in the brain of rats with thioacetamide (TAA)-induced acute liver failure. Here we show that TAA administration increases KAT-II expression in the rat cerebral cortex and the effect is mimicked in cerebral cortical astrocytes in culture treated with high (5 mM) concentration of ammonia. KAT-II expression in control and TAA-treated rats was increased by NMDAr antagonist memantine, and the effects of TAA and memantine appeared additive. In astrocytes, the NMDAr antagonist MK-801 raised KAT-II expression as well, while NMDA added alone had no effect. Glutamate decreased KAT-II mRNA level, which was attenuated by MK-801. The results suggest that stimulation of KAT-II expression during hepatic encephalopathy may be associated with a partial inactivation of astrocytic NMDAr by ammonia.

Topics: Ammonia; Analysis of Variance; Animals; Astrocytes; Brain Chemistry; Carcinogens; Chemical and Drug Induced Liver Injury; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Memantine; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Thioacetamide; Transaminases; Up-Regulation