Involvement of Indoleamine-2,3-Dioxygenase and Kynurenine Pathway in Experimental Autoimmune Encephalomyelitis in Mice

Autor: Márcia Rósula Poetini Silva, Cristiano Ricardo Jesse, Silvana Peterini Boeira, Renata Giacomeli, Micheli Stéfani Zarzecki, Leandro Cattelan Souza, Marina Prigol
Rok vydání: 2020
Předmět:
0301 basic medicine
Encephalomyelitis
Autoimmune
Experimental
Kynurenine pathway
medicine.medical_treatment
Central nervous system
Gene Expression
Inflammation
Pharmacology
Biochemistry
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Kynurenine 3-Monooxygenase
0302 clinical medicine
Oximes
medicine
Animals
Indoleamine-Pyrrole 2
3
-Dioxygenase
Enzyme Inhibitors
Indoleamine 2
3-dioxygenase
Kynurenine
Sulfonamides
business.industry
Body Weight
Experimental autoimmune encephalomyelitis
Tryptophan
General Medicine
Quinolinic Acid
medicine.disease
Peptide Fragments
Mice
Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
Cytokine
chemistry
Cytokines
Female
Myelin-Oligodendrocyte Glycoprotein
medicine.symptom
business
030217 neurology & neurosurgery
Quinolinic acid
Zdroj: Neurochemical Research. 45:2959-2977
ISSN: 1573-6903
0364-3190
Popis: The experimental autoimmune encephalomyelitis (EAE) is a model that mimics multiple sclerosis in rodents. Evidence has suggested that the activation of indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme in the kynurenine pathway (KP), plays a crucial role in inflammation-related diseases. The present study aimed to investigate the involvement of the inflammatory process and KP components in a model of EAE in mice. To identify the role of KP in EAE pathogenesis, mice received IDO inhibitor (INCB024360) at a dose of 200 mg/kg (per oral) for 25 days. We demonstrated that IDO inhibitor mitigated the clinical signs of EAE, in parallel with the reduction of cytokine levels (brain, spinal cord, spleen and lymph node) and ionized calcium-binding adaptor protein-1 (Iba-1) gene expression in the central nervous system of EAE mice. Besides, IDO inhibitor causes a significant decrease in the levels of tryptophan, kynurenine and neurotoxic metabolites of KP, such as 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) in the prefrontal cortex, hippocampus, spinal cord, spleen and lymph node of EAE mice. The mRNA expression and enzyme activity of IDO and kynurenine 3-monooxygenase (KMO) were also reduced by IDO inhibitor. These findings indicate that the inflammatory process concomitant with the activation of IDO/KP is involved in the pathogenic mechanisms of EAE. The modulation of KP is a promising target for novel pharmacological treatment of MS.
Databáze: OpenAIRE
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