**5. Conclusion**

**Figure 6.** The effects of *Ido1* gene-deficiency on depression-like behavior, changes in TRP metabolism, 5-HT, and its turnover in the frontal cortex of mice following chronic *Ifn-γ* gene expression. Original data from Ref. [47]. (a) Abnormal behavior in a forced swimming test after *Ifn-γ* gene transfer in mice was improved in *Ido1* gene deficient mice. The Y axis shows the percent value of immobility time in IFN-γ-transfected (+) mice, compared to the time (100%) in IFN-γ-transfected (−) mice (n = 8–15). (b) The level of TRP metabolites in the frontal cortex of mice 35 days after *Ifn-γ*-gene transfer (n = 6–15). (c) The amount of 5-HT, 5-HIAA, and 5-HIAA/5-HT ratio as an index of serotonin turnover in the frontal cortex of mice 35 days after *Ifn-γ*-gene transfer (n = 6–15). The open bar represents wild type and the closed bar, *Ido1* gene deficient mice. IFNγ-transfected (−) mice were injected with the control plasmid (pCpG-mcs), and IFN-γ-transfected (+) mice were injected with the IFN-γ-expressing pCpG-Muγ plasmid. Each column represents the mean ± SEM. \**p*<0.05, \*\*\**p*<0.001 *versus* IFN-γ-

50 Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors

*p*<0.05, ##*p*<0.01, ###*p*<0.001 *versus* IFN-γ-transfected (+) wild type mice [47].

transfected (−) wild type mice, #

The levels of TRP metabolites in the serum of HCV patients changed significantly. In particular, the increase in serum 3-HK concentration in depressive HCV patients was much larger than that in HCV patients without depressive symptoms. The ratios of serum KYN/ TRP, reflecting IDO1 activity, and 3-HK/KA were increased in depressive and non-depressed HCV patients with therapy. However, the increase in serum KYN/TRP and 3-HK/KA ratios in depressive patients was much higher than that of non-depressive HCV patients. When the *Ifn-γ* gene was transfected into normal mice, depression-like behavior significantly increased. Additionally, *Ifn-γ* gene transfer to mice induced dramatic changes in TRP metabolite concentrations in the serum and the prefrontal cortex. On the other hand, genetic deletion of *Ido1* abrogated the enhanced depression-like behavior after *Ifn-γ* gene transfer. In conclusion, our results clearly show that IDO1 is a critical molecular regulator of the depressive pathology induced as a side effect of interferon therapy. Moreover, the depressive symptoms are induced via increases in degradation of TRP and neuroactive metabolites along the KYN pathway, which finally changes in the alternation of 5-HT turnover. Our findings suggest that inflammatory pathways that lead to the activation of IDO1 may be a novel therapeutic target in patients suffering from inflammation-associated depression, for example, HCV or cancer therapy. Our results also suggest the monitoring of TRP-KYN metabolites during immunotherapy might assist in predicting the onset risk of depression as a side effect in these patients. However, further insight into the role of each downstream KYN pathway metabolite in the pathological process is needed to understand, and to clarify the relationship with complex neurotransmitters.

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