Investigação da via da quinurenina no modelo de encefalomielite autoimune experimental em camundongos

Abstract

Multiple sclerosis (MS) is a neurological, chronic, autoimmune disease, progressive in nature and has no cure. Combination of genetic predisposition together with toxic environmental factors can be decisive in triggering this disease. Symptoms vary between motor, sensory and cognitive. Clinical manifestations vary widely from one individual to another, being one of the problems when treating this disease. Experimental autoimmune encephalomyelitis (EAE) is a model that simulates remitting-recurrent multiple sclerosis (EMRR) in rodents. Active evidence that the activation of indoleamine-2,3-dioxigenase (IDO), an enzyme that limits the speed of the kynurenine pathway (KP), plays a crucial role in diseases related to inflammation. The present study aimed to investigate the involvement of the inflammatory process and the components of the KP in a model of EAE in mice. Understanding the influence of this pathway can enable the delimitation of therapeutic targets, as well as studying the participation of the life of quinurenine in this disease. For this, an EAE was induced by subcutaneous immunization (s.c.) with 200 μl of emulsion containing 200 μg of myelin oligodendrocyte protein peptide (MOG35-55) and 500 μg of Mycobacterium tuberculosis extract. To identify the role of VQ in the pathogenesis of EAE, the mice received the inhibitor IDO (INCB024360) at a dose of 200 mg/kg (orally) for 25 days. We demonstrated that the IDO inhibitor mitigated the clinical signs of EAE, in parallel with the reduction of cytokine levels (brain: prefrontal cortex and hippocampus, spinal cord, spleen and lymph node) and expression of the ionized calcium binding adapter gene (Iba-1) in the central nervous system of mice with EAE. In addition, the inhibitor IDO c’auses a decrease in levels of tryptophan, quinurenine and KP neurotoxic metabolites such as 3- hydroxyquinurenine (3-HK) and quinolinic acid (QUIN) in the prefrontal cortex, hippocampus, spinal cord, spleen and lymph node in mice with EAE. An mRNA expression. and an enzyme activity of IDO and quinurenine 3-monooxygenase (KMO) were also reduced by the IDO inhibitor. These findings indicate that the inflammatory process concomitant with the activation of IDO/VQ is related to the pathogenic mechanisms of EAE. A modulation of KP is a promising target for an adjunctive treatment in patients with MS.