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N-Acetylcysteine Inhibits Kynurenine Aminotransferase II.
Neuroscience ( IF 3.3 ) Pub Date : 2020-08-05 , DOI: 10.1016/j.neuroscience.2020.07.049
T Blanco-Ayala 1 , K V Sathyasaikumar 1 , J D Uys 2 , V Pérez-de-la-Cruz 3 , L S Pidugu 4 , R Schwarcz 1
Affiliation  

The tryptophan metabolite kynurenic acid (KYNA) may play an important role in normal and abnormal cognitive processes, most likely by interfering with α7 nicotinic and NMDA receptor function. KYNA is formed from its immediate precursor kynurenine either by non-enzymatic oxidation or through irreversible transamination by kynurenine aminotransferases. In the mammalian brain, kynurenine aminotransferase II (KAT II) is the principal enzyme responsible for the neosynthesis of rapidly mobilizable KYNA, and therefore constitutes an attractive target for pro-cognitive interventions. N-acetylcysteine (NAC), a brain-penetrant drug with pro-cognitive efficacy in humans, has been proposed to exert its actions by increasing the levels of the anti-oxidant glutathione (GSH) in the brain. We report here that NAC, but not GSH, inhibits KAT II activity in brain tissue homogenates from rats and humans with IC50 values in the high micromolar to low millimolar range. With similar potency, the drug interfered with the de novo formation of KYNA in rat brain slices, and NAC was a competitive inhibitor of recombinant human KAT II (Ki: 450 μM). Furthermore, GSH failed to S-glutathionylate recombinant human KAT II treated with the dithiocarbamate drug disulfiram. Shown by microdialysis in the prefrontal cortex of rats treated with kynurenine (50 mg/kg, i.p.), peripheral administration of NAC (500 mg/kg, i.p., 120 and 60 min before the application of kynurenine) reduced KYNA neosynthesis by ∼50%. Together, these results suggest that NAC exerts its neurobiological effects at least in part by reducing cerebral KYNA formation via KAT II inhibition.



中文翻译:

N-乙酰半胱氨酸抑制犬尿氨酸氨基转移酶 II。

色氨酸代谢物犬尿酸 (KYNA) 可能在正常和异常认知过程中发挥重要作用,最有可能通过干扰 α7 烟碱和 NMDA 受体功能。KYNA 由其直接前体犬尿氨酸通过非酶氧化或通过犬尿氨酸氨基转移酶的不可逆转氨作用形成。在哺乳动物的大脑中,犬尿氨酸氨基转移酶 II (KAT II) 是负责快速动员 KYNA 新合成的主要酶,因此构成了促认知干预的有吸引力的目标。N-乙酰半胱氨酸 (NAC) 是一种对人类具有促进认知功效的脑渗透药物,已被提议通过增加大脑中抗氧化谷胱甘肽 (GSH) 的水平来发挥其作用。我们在这里报告 NAC,但不是 GSH,在高微摩尔到低毫摩尔范围内有50 个值。该药物具有相似的效力,可干扰大鼠脑切片中 KYNA 的从头形成,NAC 是重组人 KAT II (Ki: 450 μM) 的竞争性抑制剂。此外,GSH 未能 S-谷胱甘肽化用二硫代氨基甲酸盐药物双硫仑治疗的重组人 KAT II。通过犬尿氨酸(50 mg/kg,ip)治疗的大鼠前额叶皮层微透析显示,外周给予 NAC(500 mg/kg,ip,在应用犬尿氨酸前 120 和 60 分钟)可减少 KYNA 新生合成约 50% . 总之,这些结果表明 NAC 至少部分通过抑制 KAT II 减少脑 KYNA 的形成来发挥其神经生物学作用。

更新日期:2020-08-30
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