Cuprizone markedly decreases kynurenic acid levels in the rodent brain tissue and plasma

Helga Polyák,Edina Katalin Cseh,Zsuzsanna Bohár,Cecilia Rajda,Dénes Zádori,Péter Klivényi,József Toldi,László Vécsei

doi:10.1016/j.heliyon.2021.e06124

Abstract

BackgroundThe kynurenine (KYN) pathway (KP) of the tryptophan (TRP) metabolism seems to play a role in the pathomechanism of multiple sclerosis (MS). Cuprizone (CPZ) treated animals develop both demyelination (DEM) and remyelination (REM) in lack of peripheral immune response, such as the lesion pattern type III and IV in MS, representing primary oligodendrogliopathy. ObjectiveTo measure the metabolites of the KP in the CPZ treated animals, including TRP, KYN and kynurenic acid (KYNA). We proposed that KYNA levels might be decreased in the CPZ-induced demyelinating phase of the animal model of MS, which model represents the progressive phase of the disease. MethodsA total of 64 C57Bl/6J animals were used for the study. Immunohistochemical (IHC) measurements were performed to prove the effect of CPZ, whereas high-performance liquid chromatography (HPLC) was used to quantify the metabolites of the KP (n = 10/4 groups; DEM, CO1, REM, CO2). ResultsIHC measurements proved the detrimental effects of CPZ. HPLC measurements demonstrated a decrease of KYNA in the hippocampus (p < 0.05), somatosensory cortex (p < 0.01) and in plasma (p < 0.001). ConclusionThis is the first evidence of marked reduction in KYNA levels in a non-immune mediated model of MS. Our results suggest an involvement of the KP in the pathomechanism of MS, which needs to be further elucidated.

Highlights

Multiple sclerosis (MS) is an immune mediated, chronic inflammatory and demyelinating disease of the central nervous system (CNS)
We proposed that kynurenic acid (KYNA) levels might be decreased in the CPZ-induced demyelinating phase of the animal model of multiple sclerosis (MS), as this the best model, which represents the progressive phase of the disease
We investigated tryptophan and the metabolites of the KP in the CPZ-induced demyelination model

Summary

Introduction

Multiple sclerosis (MS) is an immune mediated, chronic inflammatory and demyelinating disease of the central nervous system (CNS). The infiltration of CNS by peripheral immune cells (T and/or B cells) and macrophages, as well as the activation of microglia and astrocytes within the CNS, result in the exaggerated production of reactive oxygen species (ROS) and proinflammatory cytokines (Ortiz et al, 2016). Cuprizone (CPZ) treated animals develop both demyelination (DEM) and remyelination (REM) in lack of peripheral immune response, such as the lesion pattern type III and IV in MS, representing primary oligodendrogliopathy. Objective: To measure the metabolites of the KP in the CPZ treated animals, including TRP, KYN and kynurenic acid (KYNA). We proposed that KYNA levels might be decreased in the CPZ-induced demyelinating phase of the animal model of MS, which model represents the progressive phase of the disease. Our results suggest an involvement of the KP in the pathomechanism of MS, which needs to be further elucidated

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Conclusion