Hepatitis C virus, the most common blood-borne infection and a major cause of liver cirrhosis and carcinoma, is characterized by a 30 - 50% rate of depression as a side-effect of interferon (IFN)-alpha therapy, and by similarly high incidence of insulin resistance (IR), diabetes type 2 risk factor. Chronic inflammation was suggested as a common denominator for both depression and IR. Molecular mechanisms mediating impact of chronic, Th-1 type, inflammation on depression and IR are not clear. This proposal aims to explore the possibility that up-regulated formation of xanthurenic acid (XA) is associated with both IFN-alpha induced depression and IR. Pro-inflammatory factors (e.g., IFN) down-regulate tryptophan (TRP) conversion into serotonin, a major target of antidepressant action, and up-regulate TRP metabolism into kynurenine (KYN), a substrate for production of 3-hydroxyKYN (HK), a precursor of XA. Increased urine excretion of XA, and elevated serum HK were observed in major depressive disorder while normalization of XA predicted the recovery. Further metabolism of HK towards NAD+ formation, depends on pyridoxal'-5-phosphate (P5P). Inflammation reduces availability of P5P, and, thus, diverts excessively produced HK from formation of NAD+ towards production of XA. Possible mechanisms of diabetogenic effects of XA might include , an induction of pathological apoptosis of pancreatic beta cells through caspase 3-dependent mechanism. Our working hypothesis suggests that up-regulated formation of XA is a marker associated with both IFN-alpha induced depression and IR. This suggestion is partly supported by our observation of correlation (r=0.32, p=0.01) between IR and serum KYN in 60 HCV patients. However, we did not assess HK, XA and P5P, and had not enough samples to assess the correlation of XA and IR with depression. As a proof-of-concept pilot study we propose to evaluate IR, XA (and TRP, KYN and KYNA), and P5P in already collected blood samples of 300 HCV participants of our completed R21 study of IFNG(+874)T/A gene polymorphisms in IFN-alpha induced depression. Obtained results will be merged with our already collected data on incidence of IFN-alpha induced depression and serum levels of neopterin, a marker of IFN-related inflammation, that, as we reported previously,, correlates with IR and, inversely, with P5P. We will analyze associations of these markers with each other, and also with incidence of IFN-alpha induced depression. We predict positive correlations between XA and IR, and also between XA and the likelihood of having IFN-alpha associated depression. We also expect inverse correlations between XA and IR and P5P. Results of this pilot study will help to develop new tools for prevention/treatment of depression and type 2 diabetes in HCV and other conditions associated with chronic inflammation and (e.g., major depressive disorder, metabolic syndrome, obesity and aging).

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Hepatitis C virus infection is characterized by a high (54%) incidence of insulin resistance (IR), a precursor of type 2 diabetes, and by a high (30 -50%) rate of depression as a side effect of treatment with interferon-alpha. This proposal aims to find out whether increased formation of xanthurenic acid from tryptophan induced by chronic inflammation is a common mechanism for high rates of IR and depression in HCV patients.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Small Research Grants (R03)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Meinecke, Douglas L
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Tufts University
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Navrotskaya, Valeriya; Wnorowski, Artur; Turski, Waldemar et al. (2018) Effect of Kynurenic Acid on Pupae Viability of Drosophila melanogaster cinnabar and cardinal Eye Color Mutants with Altered Tryptophan-Kynurenine Metabolism. Neurotox Res 34:324-331
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Navrotskaya, Valeriya; Oxenkrug, Gregory; Vorobyova, Lyudmila et al. (2015) Attenuation of high sucrose diet-induced insulin resistance in tryptophan 2,3-dioxygenase deficient Drosophila melanogaster vermilion mutants. Integr Obes Diabetes 1:93-95
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