Kynurenines in the CNS: recent advances and new questions

Vécsei, László; Szalárdy, Levente; Fülöp, Ferenc; Toldi, József

doi:10.1038/nrd3793

Cited by 641Tryptophan and brain disordersMigraine and Headache StudiesAmino Acid Enzymes and Metabolism

Kynurenines in the CNS: recent advances and new questions

Vécsei, László, Szalárdy, Levente, Fülöp, Ferenc, Toldi, József·2013·Nature Reviews Drug Discovery

DOI 10.1038/nrd3793

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Abstract

Various pathologies of the central nervous system (CNS) are accompanied by alterations in tryptophan metabolism. The main metabolic route of tryptophan degradation is the kynurenine pathway; its metabolites are responsible for a broad spectrum of effects, including the endogenous regulation of neuronal excitability and the initiation of immune tolerance. This Review highlights the involvement of the kynurenine system in the pathology of neurodegenerative disorders, pain syndromes and autoimmune diseases through a detailed discussion of its potential implications in Huntington's disease, migraine and multiple sclerosis. The most effective preclinical drug candidates are discussed and attention is paid to currently under-investigated roles of the kynurenine pathway in the CNS, where modulation of kynurenine metabolism might be of therapeutic value.

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The kynurenine pathway has both neuroprotective metabolites and neurotoxic intermediates.
“The kynurenine pathway exhibits “double-edged sword” effects on neurons with both neuroprotective metabolites (tryptophan, kynurenic acid, and picolinic acid) and neurotoxic intermediates, including 3-hydroxykynure-nine (3-HK) that generates free radicals, 3-hydroxyanthranilic acid (3-HAA), and quinolinic acid (that induces glutamate receptor excitotoxicity) (Figure 1).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Vécsei et al., 2013
The kynurenine pathway affects neuronal function by contributing to glutamate and acetylcholine synthesis and by regulating NMDA receptor activity and free radical production.
“The kynurenine pathway modulates neuronal functions as it is involved in the synthesis of two fundamental neuro-transmitters (glutamate and acetylcholine) as well as regulates N-methyl-D-aspartate (NMDA) receptor activity and free radical production (Vécsei et al., 2013).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Vécsei et al., 2013
In mammals, the kynurenine pathway is the sole de novo route for NAD+ synthesis.
“While the aspartate pathway is the de novo NAD+ pathway in most photosynthetic eukaryotes, the kynurenine pathway is the only de novo NAD+ synthetic pathway in mammals.”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Vécsei et al., 2013
Kynurenic acid antagonizes NMDA receptors, whereas quinolinic acid agonizes them.
“While kynurenic acid is an NMDA receptor antagonist, quinolinic acid is an NMDA receptor agonist (Vécsei et al., 2013).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Vécsei et al., 2013

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Authors: Vécsei, L., Szalárdy, L., Fülöp, F., & Toldi, J.
Affiliations: University of Szeged (HU)
Corresponding author: Vécsei, László
ORCID: Vécsei, László
Szalárdy, Levente
Fülöp, Ferenc
Toldi, József
Venue: Nature Reviews Drug Discovery
Publisher: Springer Science and Business Media LLC
Published: 2012-12-14
Volume: 12
Issue: 1
Pages: 64-82
ISSN: 1474-1776 (ISSN-L)
1474-1784
DOI: 10.1038/nrd3793
OpenAlex: W1996177596
Cited by: 641
References: 234
Citations by year: 2026: 30 · 2025: 44 · 2024: 45 · 2023: 41 · 2022: 63 · 2021: 62 · 2020: 55 · 2019: 55 · 2018: 39 · 2017: 42 · 2016: 57 · 2015: 51 · 2014: 37 · 2013: 20
FWCI: 2.26
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Reviews Drug Discovery (publishedVersion)
PubMed (publishedVersion)
SZTE Publicatio Repozitórium (University of Szeged) (acceptedVersion)
Funders: Szegedi Tudományegyetem
Topics: Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Health Sciences › Medicine › Psychiatry and Mental health › Migraine and Headache Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords: kynurenine pathway, tryptophan metabolism, kynurenine, Huntington's disease, migraine, multiple sclerosis, neurodegenerative diseases, pain syndromes, autoimmune disease, neuronal excitability, immune tolerance, CNS drug candidates
MeSH terms: Animals, Autoimmune Diseases, Central Nervous System Diseases, Drug Evaluation, Preclinical, Humans, Immune Tolerance, Kynurenine, Migraine Disorders, Pain, Tryptophan, Drug Design, Neurodegenerative Diseases

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Kynurenines in the CNS: recent advances and new questions

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