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Kynurenines in the CNS: recent advances and new questions

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.

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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Figure 1: The kynurenine metabolic pathway.
Figure 2: Peripheral and central aspects of kynurenine pathway-related neuroprotective approaches.
Figure 3: Chemical structure of a potent kynurenic acid carboxamide derivative.
Figure 4: Therapeutic implications for modulation of the kynurenine pathway in Huntington's disease.
Figure 5: Possible sites of intervention in the glutamatergic model of migraine pathogenesis.
Figure 6: The double-edged sword of IDO activation in the central nervous system.

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Acknowledgements

The authors' research activities are supported by the projects titled “OTKA (K 75628) and TÁMOP-4.2.2.A-11/1KONV-2012-0052 — Creating the Centre of Excellence at the University of Szeged”.

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Supplementary information

Supplementary information S1

Kynurenine alterations and therapeutic implications in psychiatric disorders (PDF 228 kb)

Supplementary information S2

Excitotoxicity and Huntington's disease (PDF 123 kb)

Supplementary information S3

The role of glutamate in trigeminal nociception and migraine pathogenesis (PDF 127 kb)

Supplementary information S4

Molecular modelling of migraine (PDF 114 kb)

Supplementary information S5

Selected inhibitors of kynurenine aminotransferases I and II (PDF 181 kb)

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FURTHER INFORMATION

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Ferenc Fülöp's homepage

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http://www.vistagen.com/?page_id=198

EvaluatePharma website (1 August 2011) — “Results of Phase III Bravo Trial Reinforce Unique Profile of Laquinimod for Multiple Sclerosis Treatment”

VistaGen website (22 December 2010 press release)

Glossary

Huntington's disease

A dominantly inherited neurodegenerative disorder in which there is preferential loss of striatal GABA (γ-aminobutyric acid)-ergic neurons, manifesting in involuntary movements and psychic alterations, and is gradually accompanied by dystonia, pyramidal signs and dementia.

Migraine

A common primary headache characterized by spontaneous attacks of unilateral pulsating pain of moderate to severe intensity, which is aggravated by routine physical activity and generally associated with nausea as well as photo- and phonophobia.

Immunological tolerance

A process in which the immune system actively ignores an antigen and does not elicit a specific immunological attack. The 'target' of tolerance can be either autogeneic or allogeneic.

Autoimmune diseases

A collective of various clinical disorders in which the immune system fails to provide self-tolerance.

Multiple sclerosis

A chronic autoimmune neuroinflammatory disorder of the central nervous system, characterized by demyelination as well as axonal and neuronal degeneration. The disease course is progressive, generally presenting in relapses and remissions.

Mutant huntingtin

Pathognomonic huntingtin protein that develops as a result of the expansion of the CAG repeat in the huntingtin (HTT) gene, resulting in the formation of inclusion bodies and mitochondrial dysfunction. The length of the polyglutamine sequence correlates with disease severity.

3-nitropropionic acid

The most widely used mitochondrial complex II inhibitor among the neurotoxin-mediated models of Huntington's disease. It evokes preferential striatal neurodegeneration and characteristic motor symptoms in vivo.

Trigeminovascular system

An anatomical and physiological system comprising trigeminal sensory neurons that receive afferentation from meningeal blood vessels. The activation and sensitization of the trigeminovascular system is thought to have a central role in the pathomechanism of migraine.

Caudal trigeminal nucleus

A brainstem structure containing second-order trigeminal sensory neurons that receive nociceptive afferents from the trigeminal ganglia and regulatory afferents from other brainstem structures, including the locus coeruleus and nucleus raphe magnus. The activation and sensitization of this region has a key role in migraine.

Cortical spreading depression

The electrophysiological correlate of the aura phenomenon, which is a perceptual disturbance experienced by 20–25% of patients before a migraine attack.

First-order nociceptive neurons

Pseudounipolar sensory neurons in the trigeminal and dorsal root ganglia that receive noxious stimuli in the periphery and transmit these stimuli to second-order nociceptive neurons. Their functional plasticity contributes to the development of peripheral sensitization in pain syndromes.

FOS

An immediate early gene, the expression of which is widely used as a marker of neuronal activity.

NMDA hypothesis

A concept proposing that alterations in glutamatergic neurotransmission — especially those mediated by NMDA (N-methyl-D-aspartate) receptors — have a central role in the pathogenesis of migraine.

Dendritic cells

Professional antigen-presenting cells that are capable of engulfing, processing and presenting antigens to stimulate naive lymphocytes and promote adaptive immune responses. Certain subpopulations can exert potent T cell-regulatory properties.

Natural killer cells

A major component of the innate immune system. Natural killer cells are involved in the deletion of bacterial, malignantly transformed and virus-infected cells. They are not identical to natural killer T cells.

Regulatory T cells

A CD25+ and forkhead box P3-positive (FOXP3+) subtype of mature CD4+ T cells that are responsible for the suppression and inhibition of the adaptive immune response, and as such are essential in maintaining immune homeostasis and self-tolerance.

B7

A ligand that is expressed on the surface of antigen-presenting cells and is bi-directionally involved in the regulation of immune responses. The interaction of B7 with cytotoxic T lymphocyte antigen 4 (CTLA4) has been implicated in indoleamine 2,3-dioxygenase induction in dendritic cells as well as in the inhibition of T helper 17 (TH17) cell differentiation.

Experimental autoimmune encephalitis

(EAE). The prototype model for T cell-mediated autoimmune disorders. The priming of the neuroimmune system with different central nervous system (CNS)-specific antigens results in distinct models that recapitulate some of the key features of multiple sclerosis.

TH17 cells

T helper 17 cells; a recently identified CD4+ T helper subtype that expresses interleukin-17. These cells are generally associated with autoimmune disorders and also have a potential role in antitumour immune responses.

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Vécsei, L., Szalárdy, L., Fülöp, F. et al. Kynurenines in the CNS: recent advances and new questions. Nat Rev Drug Discov 12, 64–82 (2013). https://doi.org/10.1038/nrd3793

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