Role of the indoleamine-2,3-dioxygenase/kynurenine pathway of tryptophan metabolism in behavioral alterations in a hepatic encephalopathy rat model.
Role of the indoleamine-2,3-dioxygenase/kynurenine pathway of tryptophan metabolism in behavioral alterations in a hepatic encephalopathy rat model.
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DOI：
10.1186/s12974-017-1037-9
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发表时间：
2018-01-04
影响因子：
9.3
通讯作者：
Yu X
中科院分区：
文献类型：
--
作者：
Jiang X;Xu L;Tang L;Liu F;Chen Z;Zhang J;Chen L;Pang C;Yu X
本研究旨在探讨色氨酸(Try)代谢的吲哚-2，3-双加氧酶(IDO)/犬尿氨酸(KYN)途径在肝性脑病(HE)大鼠行为学改变中的作用。用QT-PCR法和ELISA法检测促炎细胞因子的表达水平，用QT-PCR法和Western印迹法检测IDOS的表达水平，用高效液相色谱法测定不同脑区5-羟色胺(5-HT)、KYN、Try、3-羟基犬尿氨酸(3-HK)和犬尿酸(KA)的水平。观察1-甲基-L-色氨酸(1-MT)对胆管结扎大鼠的认知、焦虑和抑郁样行为的影响。BDL7天后大鼠血清肿瘤坏死因子-α、IL-1β和IL-6水平升高，且早于脑内，提示外周免疫激活可能导致中枢促炎症细胞因子表达上调。此外，BDL大鼠在记忆形成以及焦虑和抑郁样行为方面表现出进行性下降。进一步研究发现，BDL后IDO表达增加，并伴有5-羟色胺的减少和KYN的增加，以及3-HK和KA的异常表达。IDO抑制剂1-MT逆转了BDL手术对上述结果的影响。这些结果提示：(1)BDL大鼠的行为障碍与促炎细胞因子有关；(2)炎症激活的KYN代谢途径可能在HE的发生发展中起重要作用；(3)1-MT可作为HE的治疗药物。本文的在线版本(10.1186/s12974-0171037-9)包含向授权用户提供的补充材料。
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. The online version of this article (10.1186/s12974-017-1037-9) contains supplementary material, which is available to authorized users.
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