Interferon (IFN)-alpha treatment of hepatitis C virus (HCV) has limited efficacy and involves frequent and severe psychiatric side-effects. Prediction of risk for depression and antiviral efficacy of IFN-alpha treatment is of great importance for bot patient wellbeing and health care expense. IFN- stimulated genes (IFN-SGs) concurrently up-regulates rate-limiting enzymes of formation of neopterin, a by-product of pteridines biosynthesis, and kynurenine (KYN), a tryptophan (TRY) metabolite. We found elevated plasma levels of neopterin in patients (HCV genotypes 2 and 3) with poor anti-viral response;and association of IFN-alpha-induced depression with a high producer allele of IFN-gamma gene that encodes production of IFN-gamma, the strongest inducer of TRY - KYN metabolism.[1] We suggest that elevated KYN/TRY ratio predicts high risk of depression and low neopterin levels predict positive anti-viral response to IFN-alpha treatment. To test this hypothesis we propose to assess neopterin, KYN and TRY levels in already collected blood samples of 300 HCV participants from our completed study of IFNG (+874) T/A gene polymorphisms in IFN-alpha-induced depression. Our study will help to develop rapid and cost-effective methods predicting the major outcomes of IFN-alpha therapy (alone and in combination with ribavirin or protease inhibitors) of HCV (and other conditions treatable with IFN-alpha, e.g., melanoma, multiple sclerosis);and help to understand the role of inflammation in major depressive disorder.

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This proposal aims to develop a rapid and reliable method for prediction of risk for depression and anti-viral efficacy of interferon-alpha treatment of hepatiti C virus patients. Method will consist of the assessment of plasma levels of markers of inflammation: neopterin, and kynurenine/tryptophan ratio.

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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Oxenkrug, Gf; Turski, Wa; Zgrajka, W et al. (2014) Disturbances of Tryptophan Metabolism and Risk of Depression in HCV Patients Treated with IFN-Alpha. J Infect Dis Ther 2:
Navrotskaya, Valeriya; Oxenkrug, Gregory; Vorobyova, Lyudmila et al. (2014) Berberine Attenuated Aging-Accelerating Effect of High Temperature in Drosophila Model. Am J Plant Sci 5:275-278
Oxenkrug, Gregory (2013) Serotonin-kynurenine hypothesis of depression: historical overview and recent developments. Curr Drug Targets 14:514-21
Oxenkrug, Gregory (2013) Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways. Mol Neurobiol 48:294-301
Oxenkrug, Gregory; Ratner, Rebecca; Summergrad, Paul (2013) Kynurenines and vitamin B6: link between diabetes and depression. J Bioinform Diabetes 1:
Oxenkrug, Gregory F; Requintina, Pura J; Mikolich, Dennis L et al. (2012) Neopterin as a marker of response to antiviral therapy in hepatitis C virus patients. Hepat Res Treat 2012:619609