1. Involvement of Indoleamine-2,3-Dioxygenase and Kynurenine Pathway in Experimental Autoimmune Encephalomyelitis in Mice
- Author
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Márcia Rósula Poetini Silva, Cristiano Ricardo Jesse, Silvana Peterini Boeira, Renata Giacomeli, Micheli Stéfani Zarzecki, Leandro Cattelan Souza, and Marina Prigol
- Subjects
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 - Abstract
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.
- Published
- 2020