title: Indoleamine-2,3-Dioxygenase/Kynurenine Pathway as a Potential Pharmacological Target to Treat Depression Associated with Diabetes.
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.
authors.affiliation: Department of Pharmacology, Federal University of Paraná, Rua Coronel H dos Santos S/N, P.O. Box 19031, Curitiba, PR, 81540-990, Brazil.
authors.forename: Isabella Caroline
authors.initials: IC
authors.lastname: da Silva Dias
authors.affiliation: Department of Physiology, Federal University of Paraná, Curitiba, PR, 81540-990, Brazil.
authors.forename: Bruno
authors.initials: B
authors.lastname: Carabelli
authors.affiliation: Department of Pharmacology, Federal University of Paraná, Rua Coronel H dos Santos S/N, P.O. Box 19031, Curitiba, PR, 81540-990, Brazil.
authors.forename: Daniela Kaori
authors.initials: DK
authors.lastname: Ishii
authors.affiliation: Department of Pharmacology, Federal University of Paraná, Rua Coronel H dos Santos S/N, P.O. Box 19031, Curitiba, PR, 81540-990, Brazil.
authors.forename: Helen
authors.initials: H
authors.lastname: de Morais
authors.affiliation: 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.
authors.forename: Milene Cristina
authors.initials: MC
authors.lastname: de Carvalho
authors.affiliation: Department of Basic Pathology, Laboratory of Neurobiology, Federal University of Paraná, Curitiba, PR, 81531-990, Brazil.
authors.forename: Luiz E
authors.initials: LE
authors.lastname: Rizzo de Souza
authors.affiliation: Department of Basic Pathology, Laboratory of Neurobiology, Federal University of Paraná, Curitiba, PR, 81531-990, Brazil.
authors.forename: Silvio M
authors.initials: SM
authors.lastname: Zanata
authors.affiliation: 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.
authors.forename: Marcus Lira
authors.initials: ML
authors.lastname: Brandão
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of São Paulo, Ribeirão Preto, SP, 14049-900, Brazil.
authors.forename: Thiago Mattar
authors.initials: TM
authors.lastname: Cunha
authors.affiliation: Department of Physiology, Federal University of Paraná, Curitiba, PR, 81540-990, Brazil.
authors.forename: Anete Curte
authors.initials: AC
authors.lastname: Ferraz
authors.affiliation: Department of Pharmacology, Federal University of Paraná, Rua Coronel H dos Santos S/N, P.O. Box 19031, Curitiba, PR, 81540-990, Brazil.
authors.forename: Joice Maria
authors.initials: JM
authors.lastname: Cunha
authors.affiliation: Department of Pharmacology, Federal University of Paraná, Rua Coronel H dos Santos S/N, P.O. Box 19031, Curitiba, PR, 81540-990, Brazil. janaina.zanoveli@ufpr.br.
authors.forename: Janaina Menezes
authors.initials: JM
authors.lastname: Zanoveli
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal; D001786:Blood Glucose / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003863:Depression / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000523:psychology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007052:Ibuprofen / Q000494:pharmacology / Q000627:therapeutic use; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism*; D008297:Male; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use; D058990:Molecular Targeted Therapy; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D013550:Swimming; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D001786:Blood Glucose; D016207:Cytokines; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018836:Inflammation Mediators; D005473:Fluoxetine; D012701:Serotonin; D007737:Kynurenine; D014364:Tryptophan; D008911:Minocycline; D007052:Ibuprofen; D009638:Norepinephrine; C525396:1-methyltryptophan
keywords: Depression; Hippocampus; Indoleamine-2,3-dioxygenase inflammation; Serotonin; Streptozotocin