Abstract
BackgroundThis 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.MethodsExpression 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.ResultsIncreased 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.ConclusionTaken 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.
Highlights
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 of proinflammatory cytokines in the brain and blood of bile duct ligation (BDL) rats To investigate the time course and regional response of proinflammatory cytokine expression following BDL surgery, messenger RNA levels of IL-1β, IL-6, and TNF-α in the hippocampus, cerebral cortex, hypothalamus, and striatum of each rat were measured 0, 7, 14, 21, and 28 days after BDL surgery. mRNA levels of TNF-α, IL-1β, and IL-6 in the hippocampus of BDL rats were significantly elevated relative to the sham group 14 days after BDL surgery (p < 0.05, p < 0.01, Fig. 2a)
Similar increases of TNF-α, IL-1β, and IL-6 mRNA expression levels were found in the cerebral cortex, hypothalamus, and striatum (p < 0.05, p < 0.01, Fig. 2b–d)
Summary
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. Hepatic encephalopathy (HE) is a neuropsychiatric abnormality in patients with acute or chronic liver disease. It is characterized by personality mood change, cognitive impairment, decreased consciousness, and coma [1, 2]. Neurological alteration in HE was affected by both hyperammonemia and inflammation [5, 6]. Hyperammonemia and inflammation act synergistically to induce depression, anxiety, and cognitive impairment, Jiang et al Journal of Neuroinflammation (2018) 15:3 as shown in the research analyzing neurological impairment in HE patients with different degrees of inflammation and hyperammonemia [8]. It was found that the inflammation induced by HE is most obvious in the hippocampus and cerebral cortex, two important brain regions regulating executive functioning, working memory, and motor planning [9,10,11]
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