Indoleamine-2,3-dioxygenase/kynurenine pathway as a potential pharmacological target to treat depression associated with diabetes

Autor: Marcus Lira Brandão, Janaina Menezes Zanoveli, Isabella Caroline da Silva Dias, Daniela Kaori Ishii, Silvio M. Zanata, Milene Cristina de Carvalho, Helen de Morais, Anete Curte Ferraz, Bruno Carabelli, Luiz Eduardo Rizzo de Souza, Thiago M. Cunha, Joice Maria da Cunha
Rok vydání: 2016
Předmět:
0301 basic medicine
Blood Glucose
Male
Kynurenine pathway
Ibuprofen
Minocycline
Weight Gain
Hippocampus
chemistry.chemical_compound
Norepinephrine
0302 clinical medicine
Molecular Targeted Therapy
Enzyme Inhibitors
Indoleamine 2
3-dioxygenase
Kynurenine
biology
Behavior
Animal
Depression
Tryptophan
Antidepressive Agents
Neurology
Cytokines
Inflammation Mediators
medicine.drug
medicine.medical_specialty
Serotonin
Serotonin reuptake inhibitor
Neuroscience (miscellaneous)
Motor Activity
Diabetes Mellitus
Experimental
03 medical and health sciences
Cellular and Molecular Neuroscience
Internal medicine
Fluoxetine
medicine
Animals
Indoleamine-Pyrrole 2
3
-Dioxygenase
Rats
Wistar
Swimming
business.industry
030104 developmental biology
Endocrinology
chemistry
biology.protein
Cyclooxygenase
business
030217 neurology & neurosurgery
Behavioural despair test
SEROTONINA
Zdroj: Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual)
Universidade de São Paulo (USP)
instacron:USP
Popis: 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.
Databáze: OpenAIRE
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