Department of Pharmacy, Zhejiang Pharmaceutical College, Ningbo, Zhejiang Province, 315000, China.
Mingzhou Hospital, Zhejiang University, Hangzhou, Zhejiang Province, 315000, China.
J Neuroinflammation. 2018 Jan 4;15(1):3. doi: 10.1186/s12974-017-1037-9.
This study aims to explore the role of indoleamine-2,3-dioxygenase (IDO)/kynurenine (KYN) pathway of tryptophan (TRY) metabolism in behavioral alterations observed in hepatic encephalopathy (HE) rats.
Expression levels of proinflammatory cytokines were tested by QT-PCR and ELISA, levels of IDOs were tested by QT-PCR and Western blot, and levels of 5-hydroxytryptamine (5-HT), KYN, TRY, 3-hydroxykynurenine (3-HK), and kynurenic acid (KA) in different brain regions were estimated using HPLC. Effects of the IDO direct inhibitor 1-methyl-L-tryptophan (1-MT) on cognitive, anxiety, and depressive-like behavior were evaluated in bile duct ligation (BDL) rats.
Increased serum TNF-α, IL-1β, and IL-6 levels were shown in rats 7 days after BDL, and these increases were observed earlier than those in the brain, indicating peripheral immune activation may result in central upregulation of proinflammatory cytokines. Moreover, BDL rats showed a progressive decline in memory formation, as well as anxiety and depressive-like behavior. Further study revealed that IDO expression increased after BDL, accompanied by a decrease of 5-HT and an increase of KYN, as well as abnormal expression of 3-HK and KA. The above results affected by BDL surgery were reversed by IDO inhibitor 1-MT treatment.
Taken together, these findings indicate that (1) behavioral impairment in BDL rats is correlated with proinflammatory cytokines; (2) TRY pathway of KYN metabolism, activated by inflammation, may play an important role in HE development; and (3) 1-MT may serve as a therapeutic agent for HE.
本研究旨在探讨色氨酸（TRY）代谢中吲哚胺 2,3-双加氧酶（IDO）/犬尿氨酸（KYN）途径在肝性脑病（HE）大鼠行为改变中的作用。
通过 QT-PCR 和 ELISA 检测促炎细胞因子的表达水平，通过 QT-PCR 和 Western blot 检测 IDO 水平，通过 HPLC 测定不同脑区 5-羟色胺（5-HT）、KYN、TRY、3-羟基犬尿氨酸（3-HK）和犬尿氨酸（KA）的水平。采用胆管结扎（BDL）大鼠评价 IDO 直接抑制剂 1-甲基-L-色氨酸（1-MT）对认知、焦虑和抑郁样行为的影响。
BDL 后 7 天大鼠血清 TNF-α、IL-1β和 IL-6 水平升高，且早于大脑中升高，表明外周免疫激活可能导致中枢促炎细胞因子上调。此外，BDL 大鼠表现出记忆形成能力下降，以及焦虑和抑郁样行为。进一步研究发现，BDL 后 IDO 表达增加，同时 5-HT 减少，KYN 增加，3-HK 和 KA 表达异常。BDL 手术引起的上述变化可被 IDO 抑制剂 1-MT 治疗逆转。
综上所述，这些发现表明：（1）BDL 大鼠的行为损伤与促炎细胞因子有关；（2）炎症激活的 KYN 代谢 TRY 途径可能在 HE 发生发展中起重要作用；（3）1-MT 可能作为 HE 的治疗药物。
