Role of the indoleamine-2,3-dioxygenase/kynurenine pathway of tryptophan metabolism in behavioral alterations in a hepatic encephalopathy rat model

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.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-1037-9) contains supplementary material, which is available to authorized users.

Water Extract from Inflorescences of Industrial Hemp Futura 75 Variety as a Source of Anti-Inflammatory, Anti-Proliferative and Antimycotic Agents: Results from In Silico, In Vitro and Ex Vivo Studies

“…3-HK and KA levels are inversely correlated in pro-inflammatory conditions, and in the present experimental paradigm the increased 3-HK/KA could be related, albeit partially, to the up-regulation of KMO [34]. In fact, the 3-HK/KA ratio could be also considered as an index of conversion of KYN in 3-HK [36], whereas the 5HIIA/5-HT represents a well-recognized index of 5-HT turnover [37]. In the present study, the LPS stimulus was not only effective in up-regulating 3-HK/KA (Figure 7), but also in decreasing 5HIIA/5-HT ( Figure 8), thus suggesting a shift of tryptophan metabolism towards the production of pro-inflammatory metabolites, in the colon, whereas the water extract was able to counteract these effects.…”

“…It is of noteworthy interest that the bioinformatics analysis predicted the potential interactions of carvacrol towards indoleamine 2,3-dioxygenase (IDO) (Supplementary Material_Bioinformatics Folder) that represents the rate limiting enzyme related to the tryptophan degradation, in the KYN pathway [38]. Interestingly, in the brain, the increased 3-HK/KA ratio following pro-inflammatory conditions was also related to the IDO up-regulation [36]. The reduction of 3-HK/KA ratio following hemp water extract treatment is paralleled by an obvious and concomitant increase in the concentration of KA, that was also suggested to exert anti-proliferative effects in colon cancer [39], with regards to the HCT116 cell line, as well [28].…”

Neuroprotective and Neuromodulatory Effects Induced by Cannabidiol and Cannabigerol in Rat Hypo-E22 cells and Isolated Hypothalamus

“…Intriguingly, both stimulating effects on 5-HT level were paralleled by a significant decrease in the 3-HK/KA ratio. Considering that pro-inflammatory conditions could activate the kinurenine pathway, thus leading to increased 3-HK/KA and 5-HT turnover [46], the inverse trend observed in the rat hypothalamus following CBD and CBG treatment suggests tryptophan degradative pathways as potential targets underlying the pharmacological effects of these compounds. In order to validate this hypothesis, a deepening further study is required to investigate the effects of CBD and CBG on kinurenine and tryptophan levels and the expression of the enzymes involved in the respective biochemical pathways.…”

Influence of Xiaoyaosan on depressive-like behaviors in chronic stress-depressed rats through regulating tryptophan metabolism in hippocampus

“…Tryptophan was an essential amino acid and a precursor substance of 5-HT. The decrease in tryptophan would lead to a decrease in 5-HT in the absence of outside intake 52. In addition, some of the metabolites of the tryptophan–kynurenine pathway such as 3-hydroxykynurenine and quinolinic acid had neurotoxic effects under the action of IDO1, which might cause the degeneration of neurons and affect the neural plasticity 53,54.…”