期刊
JOURNAL OF NEUROINFLAMMATION
卷 15, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12974-017-1037-9
关键词
Hepatic encephalopathy (HE); Inflammation; Indoleamine-2,3-dioxygenase (IDO); Serotonin (5-HT); Depression; Anxiety
资金
- scientific research project of Zhejiang Pharmaceutical College [ZPCSR2016003, ZPCSR2014009]
- Natural Science Foundation of Ningbo [2016A610239, 2017A610175]
- Zhejiang Provincial Natural Science Foundation of China [LGF18H090014]
- science and technology project of Zhejiang Medical and Health Department [2017182371]
- Scientific Research Fund of Zhejiang Provincial Education Department [Y201636660]
- Ningbo natural scientific foundation committee [2016A610238]
Background: 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. Methods: 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-Ltryptophan (1-MT) on cognitive, anxiety, and depressive-like behavior were evaluated in bile duct ligation (BDL) rats. Results: Increased serum TNF-alpha, IL-1 beta, 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. Conclusion: 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.
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