Journal Article

Kynurenines in the CNS: recent advances and new questions

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

2013

Overview

Key Points Kynurenic acid has potentially neuroprotective actions, such as antagonism at NMDA ( N -methyl- D -aspartate) receptors, inhibition of glutamate release and free radical scavenging. Pharmacological manipulations to harness the beneficial effects of this blood–brain barrier-impermeable agent include increasing the availability of its precursor L -kynurenine, modulation of the kynurenine pathway enzymes towards the synthesis of kynurenic acid, as well as the systemic administration of kynurenic acid analogues that have improved pharmacokinetic characteristics. Most of the kynurenines are neuroactive; they have important roles in the functioning of glutamate receptors and in free radical production. NMDA receptor-mediated excitotoxicity and excessive free radical production are involved in neurodegenerative diseases such as Huntington's disease. The kynurenine pathway is altered in Huntington's disease to favour the production of toxic metabolites, and the possible therapeutic potential of its pharmacological modulation is currently under experimental investigation. Glutamatergic neurotransmission is essential for the spinal and trigeminal processing of pain. Kynurenic acid has several antiglutamatergic properties. Therefore, the elevation of kynurenic acid levels could have therapeutic value in pain syndromes, including migraine. In this disorder, increases in kynurenic acid levels could suppress trigeminal and higher-order nociceptive neurons, modulate migraine generator nuclei in the brainstem and inhibit cortical spreading depression. The activation of indoleamine 2,3-dioxygenase triggers a complex immunomodulatory response, which is involved in the mediation of physiological and pathological immune tolerance. The immunosuppressive effect of this enzyme is attributable to tryptophan depletion and the actions of downstream kynurenine metabolites. There is evidence to indicate that indoleamine 2,3-dioxygenase is activated in several inflammatory and autoimmune conditions, most probably serving as a self-protecting mechanism. Experimental and indirect evidence suggests that the kynurenine pathway is overactivated in multiple sclerosis. As most of the immunotolerogenic metabolites of the kynurenine pathway exert neurotoxic and/or oligotoxic properties, the influence of this phenomenon on the pathogenesis and progression of multiple sclerosis necessitates further investigation. In experimental models of multiple sclerosis, the activation of indoleamine 2,3-dioxygenase has shown beneficial effects; indeed, this mechanism may underlie the therapeutic potential of interferon-β in multiple sclerosis. Structurally similar synthetic derivatives of kynurenines have shown disease-modifying effects in recent clinical trials. The complex anti-inflammatory and neuroprotective properties of kynurenic acid and its analogues suggest that experimental screening of such compounds is warranted. Most metabolites of the kynurenine pathway — which metabolizes tryptophan — are neuroactive. This Review describes the role of the kynurenine pathway in the pathology of Huntington's disease, migraine and multiple sclerosis, and highlights the most promising compounds that could be of therapeutic value. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/436/1729 / 631/443/319 / 692/698/1688/1366 / 89 / Animals / Autoimmune Diseases - drug therapy / Autoimmune Diseases - physiopathology / Biomedical and Life Sciences / Biomedicine / Biotechnology / Cancer Research / Care and treatment / Cellular signal transduction / Central Nervous System Diseases - drug therapy / Central Nervous System Diseases - physiopathology / Drug Design / Drug Evaluation, Preclinical / Genetic aspects / Humans / Immune Tolerance / Kynurenine - metabolism / Medicinal Chemistry / Methyl aspartate / Migraine Disorders - drug therapy / Migraine Disorders - physiopathology / Molecular Medicine / Nervous system diseases / Neurodegenerative Diseases - drug therapy / Neurodegenerative Diseases - physiopathology / Pain - drug therapy / Pain - physiopathology / Pharmacology/Toxicology / Physiological aspects / review-article / Tryptophan / Tryptophan - metabolism