An expanding range of targets for kynurenine metabolites of tryptophan

TL;DR: The increasing range of molecular targets for components of the kynurenine pathway in both the nervous and immune systems in relation to their relevance to disease and drug development are highlighted.

About: This article is published in Trends in Pharmacological Sciences.The article was published on 2013-02-01 and is currently open access. It has received 269 citations till now. The article focuses on the topics: Kynurenine pathway & Kynurenine.

Summary

The kynurenine pathway

• Apart from the tryptophan used in protein synthesis, most of this amino acid in mammals is oxidised along the kynurenine pathway.
• Only around 1% of tryptophan is used for the synthesis of 5-hydroxytrpytamine (5-HT).
• These two compounds have been the focus of attention on the kynurenine pathway for over 30 years [3,4].
• The key enzymes, indoleamine-2,3-dioxygenase (IDO) and kynurenine-3-monoxygenase (KMO) are also potential drug targets.
• The aim of this review is to highlight the increasing range of molecular targets now recognised in the nervous and immune systems in relation to their relevance to disease and drug development.

Quinolinic acid

• In addition to its ability to activate NMDARs selectively, quinolinic acid can generate reactive oxygen species (ROS).
• This activity can produce substantial oxidation of cellular lipids, especially in the presence of transition metal ions [5].
• The axon-sparing neuronal loss produced by quinolinic acid in vivo may be due partly to formation of ROS [6] although it certainly also involves activation of NMDARs.
• Acting on human primary astrocytes, excitotoxic concentrations of quinolinic acid can also promote the expression and secretion of some of the more potent chemokines and proinflammatory cytokines responsible for orchestrating the early phases of innate immune responses.
• The amyloid plaques found in the brains of patients with AD are associated with high concentrations of quinolinic acid [9] but the compound is also colocalised with hyperphosphorylated tau proteins which form the paired helical filaments in this disorder [10].

Kynurenic acid

• Two early studies of the anti-epileptic actions of kynurenic acid independently reported that its suppression of epileptiform bursts in hippocampal slices could not be entirely explained by blockade of NMDARs [11,12] (Figure 2).
• In addition, kynurenic acid produced endogenously within brain slices from kynurenine is better able to block NMDAR and 7NR than kynurenic acid which is added exogenously [15], so that its physiological activity at this site may be underestimated.
• This was associated with a reduction in the loss of synapses in the brain, with improved memory in a spatial learning task and reduced anxiety behaviour [20].
• Patients also exhibit reduced levels of kynurenic acid in the brain [24], although 3HAA concentrations are raised, consistent with the increased concentrations of quinolinic acid found in the brains of animal models of HD [25,26].
• In schizophrenia, the suppression of dopaminergic function by neuroleptic drugs can reduce the early, positive symptoms which are caused by overactivity of the ventral tegmental projections to the striatum and nucleus accumbens.

GPR35

• Another target of kynurenic acid may be the erstwhile orphan G-proteincoupled receptor GPR35, at which kynurenic acid is one of the most potent endogenous agonists yet identified [42] (Figure 2).
• The receptor has been implicated in several aspects of gastrointestinal dysfunction including the development of gastric cancer [44].
• The agonist activity of kynurenic acid could therefore be important in the early development of the CNS.
• A proposed intracellular mechanism for this effect is the lowering of intracellular calcium, mediated by GPR35-linked adenylate cyclase inhibition and reduced intracellular cAMP; a similar explanation has been advanced to explain reduced calcium-dependent release of glutamate from GPR35-expressing glia treated with kynurenic acid [42].
• There is currently little information available about other immune system cells that express GPR35, except for invariant natural killer cells (iNKT) which, on specific stimulation by glycolipids (presented by antigen presenting cells) produce a large variety of cytokines and chemokines [49]; GPR35 engagement by kynurenic acid downregulates IL-4 but not IFN- and probably has other actions yet to be identified.

Growth factors

• The same blocking action can protect the brain against the excitotoxic effects of abnormally high glutamate receptor activation.
• This protective activity may be enhanced by effects on growth factors since kynurenic acid can increase the expression of nerve growth factor (NGF) in glial cells [50,51].
• NGF is of special importance because of its regulation of proliferation and subsequent maintenance of cholinergic neurones in the CNS, and hence of relevance to AD and schizophrenia [52].
• In contrast, kynurenic acid reduced the release of fibroblast growth factor-1 (FGF1) in several different experimental models [53], so that its net effects on cell viability may depend on a balance of changes in different growth factors.
• Because kynurenic acid can enhance proliferation of some glial cells, it would be of value to examine the expression and release of gliotropic factors as well as brain-derived growth factor (BDNF).

A kynurenine receptor?

• A most surprising discovery has been that kynurenine itself – a compound regarded as being almost devoid of biological activity – can act at the aryl hydrocarbon receptor (AHR) [54] (Figure 3).
• In vertebrates, the role of AHR in development extends to the maturation of cells in the immune and nervous systems.
• DCs and naïve T cells suppressed differentiation of the latter into Treg cells, while addition of kynurenine to this system restored differentiation into anti-inflammatory Treg cells and reduced differentiation into the highly inflammatory Th17 cells [55].
• Finally, it should be noted that, in addition to kynurenine, kynurenic acid may also be an agonist at the AHR with nanomolar potency [65], able to induce expression of the multi-functional and tumour-associated cytokine IL-6 (Figures 3, 4).
• The 3-hydroxy compounds Both 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3HAA) (Figure 1) show significant cellular toxicity.

A wider role in the immune system

• In addition to the effects that kynurenines have on immune function via the AHRs, there is increasing evidence for more generalised actions on the immune system.
• By inhibiting IDO, therefore, this tryptophan depletion could not be induced and T cell attack proceeded successfully to destroy the foetus.
• Overall, the increased numbers of Foxp3+Treg cells, involving the expression of IDO activity, suppresses immune function and generates a pronounced anti-inflammatory effect.
• In addition to stimulating TGF- production, 3-HAA acts directly upon Th1 cells to suppress their pro-inflammatory activity, but has no discernible action on Th2 cells [78-80] although IDO activation overall may promote Th2 function [81].
• The resulting state of immune tolerance seems to be produced by the kynurenine metabolites rather than by tryptophan depletion.

Kynurenines and drug development

• The discovery that kynurenine-derived metabolites of tryptophan could modulate the level of glutamate receptor activation focussed early interest on their potential roles in neurodegenerative disorders in which over- or underactivity of those receptors could produce excitotoxicity and neurodegeneration, or a general suppression of excitatory neurotransmission respectively.
• In schizophrenia, the contrary situation is encountered, with raised kynurenic acid levels that could be normalised by development of selective inhibitors of KAT II [21].
• The potential value of the kynurenine pathway for the development of new drugs acting in disorders such as these, in which a degree of neuronal damage is involved, has been discussed previously [90].
• In addition, the identification of a range of molecular targets such as GPR35, with potential roles in inflammatory disorders, raises the possibility of developing new generations of anti-inflammatory compounds based on the chemical structure of kynurenic acid.

Legends

• A summary of the main compounds which constitute the kynurenine pathway for the oxidative metabolism of tryptophan.
• The pathway is usually referred to in this way after the initial stable product of tryptophan oxidation, kynurenine, which was originally isolated from canine urine in the nineteenth century and named to reflect this.
• Increasing interest is being shown in a range of sites in the immune system with potential importance in the regulation of immune tolerance and cancer suppression.
• Potential sites at which kynurenine, for long regarded as biologically inactive, may act to regulate the balance of cells produced in the immune system.
• Figure 2 Figure 3 Figure 4 Abbreviations 7NR: 7-nicotinic cholinoceptors AHR: aryl hydrocarbon receptor AMPA: -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid CD8+ : cytotoxic (anti-tumour) T cells CSF : cerebrospinal fluid DC: Dendritic cells GPR35: G-protein-coupled receptor 35.

Figures

Figure 1 A summary of the main compounds which constitute the kynurenine pathway for the oxidative metabolism of tryptophan. The pathway is usually referred to in this way after the initial stable product of tryptophan oxidation, kynurenine, which was originally isolated from canine urine in the nineteenth century and named to reflect this.

Frequently asked questions

Q1. What is the role of quinolinic acid in the synthesis of tryptophan?

Quinolinic acid is an agonist at N-methyl-D-aspartate receptors (NMDAR), but is also pro-oxidant, has immunomodulatory actions and promotes the formation of hyperphosphorylated tau proteins. 

Q2. What are the future works in this paper?

Although the links between tryptophan metabolism to kynurenines and to 5- HT should not be forgotten, future research might benefit greatly from an increasing attention on the oxidative metabolism of tryptophan along the kynurenine pathway. The potential sites for interference may be under- or overactivated by their ligands, mutated genetically or modified epigenetically and should be regarded as druggable targets for pharmacological development with therapeutic value in a range of disorders in the nervous and immune systems. 

Q3. What is the role of kynurenine in the immune system?

Since kynurenine is generated when IDO or TDO are activated in pro-inflammatory microenvironments by mediators such as IFN- or TNF-, thediscovery of AHR as a kynurenine or kynurenic acid receptor may help to provide the sought-after link between chronic tissue inflammation and the induction of cancer. 

Q4. What is the effect of kynurenic acid on the prefrontal cortex?

The administration of kynurenic acid (directly or via its precursor, kynurenine), produces a reduction of extracellular dopamine concentrations, as seen in the prefrontal cortex in schizophrenia. 

Q5. What is the role of 3-HAA in the synthesis of nitric oxide?

3-HAA also inhibits nitric oxide synthase in macrophages [67] and canreadily be nitrosylated to oxadiazole compounds, a property shared with 3-HK [68]. 

Q6. What is the role of quinolinic acid in the development of disease?

Kynurenine metabolites and their receptors in diseaseIn addition to its ability to activate NMDARs selectively, quinolinic acid cangenerate reactive oxygen species (ROS). 

Q7. What is the role of quinolinic acid in the development of axon-?

Acting on human primary astrocytes, excitotoxic concentrations of quinolinic acid can also promote the expression and secretion of some of the more potent chemokines and proinflammatory cytokines responsible for orchestrating the early phases of innate immune responses. 

Q8. What is the effect of IDO on the growth and proliferation of fibroblasts?

The inhibitory effect of IFN- on the growth and proliferation ofToxoplasma parasites cultured with fibroblasts results from its activation of the first enzyme in the kynurenine pathway – IDO [74]. 

Q9. What is the role of kynurenic acid in Huntington's disease?

In addition, the identification of a range of molecular targets such as GPR35,with potential roles in inflammatory disorders, raises the possibility of developing new generations of anti-inflammatory compounds based on the chemical structure of kynurenic acid. 

Q10. What was the first specific site of action of NMDA receptors identified?

The blockade of NMDA receptors was the first specific site of action to be identified [2], followed nearly 20 years later by blockade of 7 nicotinic receptors [13]. 

Q11. What is the role of IDO in the immune system?

Although IDO is widely distributed in many tissues, the closely relatedenzyme tryptophan-2,3-dioxygenase (TDO) is largely confined to the liver. 

Q12. What are the main features of the kynurenine pathway?

In addition to the effects of kynurenic acid andkynurenine itself, some features of the kynurenine pathway on the balance of inflammatory status are mediated by 3-hydroxykynurenine and 3- hydroxyanthranilic acid (3HAA). 

Q13. What is the mechanism of the state of tolerogenesis?

The resulting state of immunetolerance (tolerogenesis) seems to be produced by the kynurenine metabolites rather than by tryptophan depletion. 

Q14. What is the effect of kynurenic acid on neuroprotective activity?

This protective activity may be enhanced by effects on growth factors since kynurenic acid can increase the expression of nerve growth factor (NGF) in glial cells [50,51]. 

Q15. What is the potential value of the kynurenine pathway for the development of new?

The potential value of the kynurenine pathway for the development of new drugs acting in disorders such as these, in which a degree of neuronal damage is involved, has been discussed previously [90] 

Q16. What is the role of kynurenines in the immune system?

In addition to the effects that kynurenines have on immune function via theAHRs, there is increasing evidence for more generalised actions on the immunesystem. 

Q17. What is the role of kynurenic acid in the immune system?

In parallel with work on the central nervous system (CNS), however, there has been growing interest in the role of kynurenines in the immune system, and the last few years have seen the identification of more molecular targets acted on by quinolinic acid, kynurenic acid or other components of the pathway.