The online version of this article (https://doi.org/10.1186/s12974-017-1037-9) contains supplementary material, which is available to authorized users.
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.
Additional file 1: Figure S1. Effects of IDO inhibitor 1-MT (1, 3 mg/kg) on locomotor activity induced by BDL in rats. Locomotor activity was assessed by total number of counts recorded for 10 min in BDL animals in different days (0d, 7d, 14d, 21d and 28d) after surgery. Data are expressed as mean ± SEM (n = 8). ***p < 0.001 when compared to the sham group. (TIFF 3600 kb)12974_2017_1037_MOESM1_ESM.tif
Additional file 2: Figure S2. Effects of IDO inhibitor 1-MT (1, 3 mg/kg) on IDO1 expression in the hippocampus in different days (0d, 7d, 14d, 21d and 28d) after BDL surgery. Data are expressed as mean ± SEM (n = 6). ***p < 0.001 when compared to the sham group, #p < 0.05 when compared to the BDL group. (TIFF 3600 kb)12974_2017_1037_MOESM2_ESM.tif
Additional file 3: Figure S3. Effects of IDO inhibitor 1-MT (1, 3 mg/kg) on IDO1 expression in the cerebral cortex in different days (0d, 7d, 14d, 21d and 28d) after BDL surgery. Data are expressed as mean ± SEM (n = 6). *p < 0.05 and **p < 0.01 when compared to the sham group, #p < 0.05 when compared to the BDL group. (TIFF 3600 kb)12974_2017_1037_MOESM3_ESM.tif
Additional file 4: Figure S4. Effects of IDO inhibitor 1-MT (1, 3 mg/kg) on KYN/TRY ratio in the hippocampus (A) and cerebral cortex (B), and 5-HT/TRY ratio in the hippocampus (C) and cerebral cortex (D) of BDL rats. Data are expressed as mean ± SEM (n = 6). *p < 0.05, **p < 0.01 and ***p < 0.001 when compared to the sham group, #p < 0.05 when compared to the BDL group. (TIFF 3600 kb)12974_2017_1037_MOESM4_ESM.tif
Additional file 5: Figure S5. Effects of IDO inhibitor 1-MT (1, 3 mg/kg) on 5-HIAA/5-HT ratio and 3-HK/KA ratio in the hippocampus (A, C) and cerebral cortex (B, D) of BDL rats. Data are expressed as mean ± SEM (n = 6). *p < 0.05, **p < 0.01 and ***p < 0.001 when compared to the sham group, #p < 0.05 when compared to the BDL group. (TIFF 3600 kb)12974_2017_1037_MOESM5_ESM.tif
Additional file 6: Figure S6. Effects of IDO inhibitor 1-MT (1, 3 mg/kg) on QA levels in the hippocampus (A) and cerebral cortex (B) of BDL rats. Data are expressed as mean ± SEM (n = 6). *p < 0.05, **p < 0.01 and ***p < 0.001 when compared to the sham group. (TIFF 3600 kb)12974_2017_1037_MOESM6_ESM.tif
Additional file 7: Table S1. Effect of 28 days 1-MT treatment on liver function tests in sham and BDL rats. (DOCX 17 kb)12974_2017_1037_MOESM7_ESM.docx
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