The tryptophan (Trp) metabolite kynurenic acid (KYNA) is an α7-nicotinic and N-methyl-d-aspartate receptor antagonist. Elevated brain KYNA levels are commonly seen in psychiatric disorders and neurodegenerative diseases and may be related to cognitive impairments. Recently, we showed that N-acetylcysteine (NAC) inhibits kynurenine aminotransferase II (KAT II), KYNA’s key biosynthetic enzyme, and reduces KYNA neosynthesis in rats in vivo. In this study, we examined if repeated systemic administration of NAC influences brain KYNA and cognitive performance in mice. Animals received NAC (100 mg/kg, i.p.) daily for 7 days. Redox markers, KYNA levels, and KAT II activity were determined in the brain. We also assessed the effect of repeated NAC treatment on Trp catabolism using brain tissue slices ex vivo. Finally, learning and memory was evaluated with and without an acute challenge with KYNA’s bioprecursor L-kynurenine (Kyn; 100 mg/kg). Subchronic NAC administration protected against an acute pro-oxidant challenge, decreased KYNA levels, and lowered KAT II activity and improved memory both under basal conditions and after acute Kyn treatment. In tissue slices from these mice, KYNA neosynthesis from Trp or Kyn was reduced. Together, our data indicate that prolonged treatment with NAC may enhance memory at least in part by reducing brain KYNA levels.

中文翻译：

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亚慢性N-乙酰半胱氨酸治疗可降低小鼠脑动尿酸水平并提高认知能力

色氨酸（Trp）代谢物动尿酸（KYNA）是α7烟碱和N-甲基-d-天冬氨酸受体拮抗剂。升高的大脑KYNA水平常见于精神疾病和神经退行性疾病，并且可能与认知障碍有关。最近，我们发现N-乙酰半胱氨酸（NAC）抑制KYNA的关键生物合成酶犬尿氨酸转氨酶II（KAT II），并减少了体内大鼠KYNA的新合成。。在这项研究中，我们检查了NAC的反复全身给药是否会影响小鼠的大脑KYNA和认知能力。动物每天接受NAC（100 mg / kg，ip），共7天。确定大脑中的氧化还原标记，KYNA水平和KAT II活性。我们还使用离体脑组织切片评估了反复NAC治疗对Trp分解代谢的影响。最后，在有和没有KYNA的生物前体L-犬尿氨酸（Kyn； 100 mg / kg）的急性挑战下，评估学习和记忆。在基础条件下和急性Kyn治疗后，亚慢性NAC给药可抵抗急性促氧化剂攻击，降低KYNA水平，降低KAT II活性并改善记忆。在这些小鼠的组织切片中，来自Trp或Kyn的KYNA新合成减少。总之，我们的数据表明，长期使用NAC治疗可能至少部分通过降低大脑KYNA水平来增强记忆。