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Indoleamine-2,3-Dioxygenase/Kynurenine Pathway as a Potential Pharmacological Target to Treat Depression Associated with Diabetes

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Abstract

Diabetes is a chronic disease associated with depression whose pathophysiological mechanisms that associate these conditions are not fully elucidated. However, the activation of the indoleamine-2,3-dioxygenase (IDO), an enzyme that participate of the tryptophan metabolism leading to a decrease of serotonin (5-HT) levels and whose expression is associated with an immune system activation, has been proposed as a common mechanism that links depression and diabetes. To test this hypothesis, diabetic (DBT) and normoglycemic (NGL) groups had the cytokines (TNFα, IL-1β, and IL-6) and 5-HT and norepinephrine (NE) levels in the hippocampus (HIP) evaluated. Moreover, the effect of the selective serotonin reuptake inhibitor fluoxetine (FLX), IDO direct inhibitor 1-methyl-tryptophan (1-MT), anti-inflammatory and IDO indirect inhibitor minocycline (MINO), or non-selective cyclooxygenase inhibitor ibuprofen (IBU) was evaluated in DBT rats submitted to the modified forced swimming test (MFST). After the behavioral test, the HIP was obtained for IDO expression by Western blotting analysis. DBT rats exhibited a significant increase in HIP levels of TNFα, IL-1β, and IL-6 and a decrease in HIP 5-HT and NA levels. They also presented a depressive-like behavior which was reverted by all employed treatments. Interestingly, treatment with MINO, IBU, or FLX but not with 1-MT reduced the increased IDO expression in the HIP from DBT animals. Taken together, our data support our hypothesis that neuroinflammation in the HIP followed by IDO activation with a consequent decrease in the 5-HT levels can be a possible pathophysiological mechanism that links depression to diabetes.

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Acknowledgments

This study was supported by grants from CNPq (Casadinho/PROCAD Grant No. 479526/2012-5). The authors thank Prof. Dr. Maria ABF Vital for kind donation of the ibuprofen and minocycline and also the technical assistance of Giuliana Bertozi during the cytokine measurement by ELISA method.

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Authors and Affiliations

  1. Department of Pharmacology, Federal University of Paraná, Rua Coronel H dos Santos S/N, P.O. Box 19031, Curitiba, PR, 81540-990, Brazil

    Isabella Caroline da Silva Dias, Daniela Kaori Ishii, Helen de Morais, Joice Maria Cunha & Janaina Menezes Zanoveli

  2. Department of Physiology, Federal University of Paraná, Curitiba, PR, 81540-990, Brazil

    Bruno Carabelli & Anete Curte Ferraz

  3. Institute of Neurosciences and Behavior (INeC) and Laboratory of Neuropsychopharmacology of Faculty of Philosophy, Sciences and Letters of University of São Paulo, Ribeirão Preto, SP, 14040-901, Brazil

    Milene Cristina de Carvalho & Marcus Lira Brandão

  4. Department of Basic Pathology, Laboratory of Neurobiology, Federal University of Paraná, Curitiba, PR, 81531-990, Brazil

    Luiz E. Rizzo de Souza & Silvio M. Zanata

  5. Department of Pharmacology, Faculty of Medicine, University of São Paulo, Ribeirão Preto, SP, 14049-900, Brazil

    Thiago Mattar Cunha

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  1. Isabella Caroline da Silva Dias
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da Silva Dias, I.C., Carabelli, B., Ishii, D.K. et al. Indoleamine-2,3-Dioxygenase/Kynurenine Pathway as a Potential Pharmacological Target to Treat Depression Associated with Diabetes. Mol Neurobiol 53, 6997–7009 (2016). https://doi.org/10.1007/s12035-015-9617-0

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