Indoleamine-2,3-Dioxygenase/Kynurenine Pathway as a Potential Pharmacological Target to Treat Depression Associated with Diabetes Isabella Caroline da Silva Dias 1 & Bruno Carabelli 2 & Daniela Kaori Ishii 1 & Helen de Morais 1 & Milene Cristina de Carvalho 3 & Luiz E. Rizzo de Souza 4 & Silvio M. Zanata 4 & Marcus Lira Brandão 3 & Thiago Mattar Cunha 5 & Anete Curte Ferraz 2 & Joice Maria Cunha 1 & Janaina Menezes Zanoveli 1 Received: 10 July 2015 /Accepted: 7 December 2015 # Springer Science+Business Media New York 2015 Abstract Diabetes is a chronic disease associated with de- pression whose pathophysiological mechanisms that associate these conditions are not fully elucidated. However, the activa- tion of the indoleamine-2,3-dioxygenase (IDO), an enzyme that participate of the tryptophan metabolism leading to a de- crease of serotonin (5-HT) levels and whose expression is associated with an immune system activation, has been pro- posed as a common mechanism that links depression and di- abetes. 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 be- havior which was reverted by all employed treatments. Inter- estingly, 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 possi- ble pathophysiological mechanism that links depression to diabetes. Keywords Streptozotocin . Serotonin . Depression . Indoleamine-2,3-dioxygenase inflammation . Hippocampus Introduction Diabetes, a metabolic condition characterized by chronic hy- perglycemia [1], is considered one of the most common met- abolic disease worldwide [2–4]. An important feature of dia- betes is its ability to develop comorbidities, such as heart disease [5], retinopathy [6], neuropathic pain, for review, please see [7], and psychiatric disorders [8]. Among the psy- chiatric comorbidities associated with both types 1 and 2 dia- betes, depression is the most studied [8–12] and is character- ized by depressed mood, anhedonia, reduced energy, feelings Electronic supplementary material The online version of this article (doi:10.1007/s12035-015-9617-0) contains supplementary material, which is available to authorized users. * Janaina Menezes Zanoveli janaina.zanoveli@ufpr.br 1 Department of Pharmacology, Federal University of Paraná, Rua Coronel H dos Santos S/N, P.O. Box 19031, Curitiba, PR 81540-990, Brazil 2 Department of Physiology, Federal University of Paraná, Curitiba, PR 81540-990, Brazil 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 4 Department of Basic Pathology, Laboratory of Neurobiology, Federal University of Paraná, Curitiba, PR 81531-990, Brazil 5 Department of Pharmacology, Faculty of Medicine, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil Mol Neurobiol DOI 10.1007/s12035-015-9617-0