Dynamic changes in kynurenine pathway metabolites in multiple sclerosis: A systematic review

Abstract

BackgroundMultiple sclerosis (MS) is a debilitating neurodegenerative disorder characterized by axonal damage, demyelination, and perivascular inflammatory lesions in the white matter of the central nervous system (CNS). Kynurenine pathway (KP), which is the major route of tryptophan (TRP) metabolism, generates a variety of neurotoxic as well as neuroprotective compounds, affecting MS pathology and the severity of impairments. Alterations in KP have been described not only in MS, but also in various psychiatric and neurodegenerative diseases. The purpose of this systematic review is to investigate the previously reported dysregulation of KP and differences in its metabolites and enzymes in patients with MS compared to healthy control subjects.MethodElectronic databases of PubMed, Scopus, Cochrane Database of Systematic Reviews, and Web of Science were searched to identify studies measuring concentrations of KP metabolites and enzymes in MS patients and control subjects. The following metabolites and enzymes implicated in the KP were investigated: TRP, kynurenine (KYN), kynurenic acid (KYNA), quinolinic acid (QUIN), picolinic acid (PIC), hydroxyindoleacetic acid (HIAA), indoleamine 2,3-dioxygenase (IDO), kynurenine aminotransferase (KAT), and their related ratios.ResultTen studies were included in our systematic review. Our review demonstrates that IDO expression is reduced in the peripheral blood mononuclear cells (PBMCs) of MS patients compared to healthy controls. Also, increased levels of QUIN and QUIN/KYNA in the serum and cerebrospinal fluid (CSF) of MS patients is observed. Differences in levels of other metabolites and enzymes of KP are also reported in some of the reviewed studies, however there are discrepancies among the included reports.ConclusionThe results of this investigation suggest a possible connection between alterations in the levels of KP metabolite or enzymes and MS. QUIN levels in CSF were higher in MS patients than in healthy controls, suggesting that QUIN may be involved in the pathogenesis of MS. The data indicate that differences in the serum/blood or CSF levels of certain KP metabolites and enzymes could potentially be used to differentiate between MS patients and control subjects.

Profile and potential role of novel metabolite biomarkers, especially indoleacrylic acid, in pathogenesis of neuromyelitis optica spectrum disorders

“…The conversion from KYN to KYNA was catalyzed via kynurenic aminotransferase (KAT), in which KYNA acted as a neuroprotective agent under physiological conditions. Decreases in KAT enzyme activities were correlated with lower levels of KYNA in the brain section of multiple sclerosis patients ( Fathi et al, 2022 ). We deduced that it may be a similar situation in NMOSD patients.…”

The Influence of Kynurenine Metabolites on Neurodegenerative Pathologies

“…Kynurenines negatively impact glutamatergic neurotransmission and exhibit direct toxic effects on neurons and glial cells, both of which are known to be damaged in the pathophysiology of multiple sclerosis. Furthermore, another intermediate metabolite of the kynurenine pathway, quinolinic acid, is considered an established neurotoxic agent [75].…”

“…KP metabolites are directly toxic to glia and neurons [77]. The activation of the KP pathway results in changing levels of kynurenine metabolites, and elevated levels of these metabolites have been found in the cerebrospinal fluid (CSF) of patients presenting with all types of MS [75]. When it comes to understanding the intricate connections between types of multiple sclerosis, the kynurenine pathway provides valuable insights into the underlying mechanisms of the disease, offering potential avenues for therapeutic interventions and the development of targeted treatments to alleviate the impact of MS on affected individuals.…”

A Decade of Dedication: Pioneering Perspectives on Neurological Diseases and Mental Illnesses

“…Anomalies in the tryptophan (Trp)-kynurenine (KYN) metabolic system have been detected in individuals with MS [131][132][133]. However, the specific profile of KYN metabolites in progressive MS is still uncertain.…”