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Although the central nervous system (CNS) and immune system were regarded as independent entities, it is now clear that immune system cells can influence the CNS, and neuroglial activity influences the immune system. Despite the many clinical implications for this 'neuroimmune interface', its detailed operation at the molecular level remains unclear. This narrative review focuses on the metabolism of tryptophan along the kynurenine pathway, since its products have critical actions in both the nervous and immune systems, placing it in a unique position to influence neuroimmune communication. In particular, since the kynurenine pathway is activated by pro-inflammatory mediators, it is proposed that physical and psychological stressors are the stimuli of an organismal protective reflex, with kynurenine metabolites as the effector arm co-ordinating protective neural and immune system responses. After a brief review of the neuroimmune interface, the general perception of tryptophan metabolism along the kynurenine pathway is expanded to emphasize this environmentally driven perspective. The initial enzymes in the kynurenine pathway include indoleamine-2,3-dioxygenase (IDO1), which is induced by tissue damage, inflammatory mediators or microbial products, and tryptophan-2,3-dioxygenase (TDO), which is induced by stress-induced glucocorticoids. In the immune system, kynurenic acid modulates leucocyte differentiation, inflammatory balance and immune tolerance by activating aryl hydrocarbon receptors and modulates pain via the GPR35 protein. In the CNS, quinolinic acid activates N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors, whereas kynurenic acid is an antagonist: the balance between glutamate, quinolinic acid and kynurenic acid is a significant regulator of CNS function and plasticity. The concept of kynurenine and its metabolites as mediators of a reflex coordinated protection against stress helps to understand the variety and breadth of their activity. It should also help to understand the pathological origin of some psychiatric and neurodegenerative diseases involving the immune system and CNS, facilitating the development of new pharmacological strategies for treatment., (© 2023 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Lymphocytes maturing in the thymus (T cells) are key factors in adaptive immunity and the regulation of inflammation. The kynurenine pathway of tryptophan metabolism includes several enzymes and compounds that can modulate T cell function, but manipulating these pharmacologically has not achieved the expected therapeutic activity for the treatment of autoimmune disorders and cancer. With increasing knowledge of other pathways interacting with kynurenines, the expansion of screening methods, and the application of virtual techniques to understanding enzyme structures and mechanisms, details of interactions between kynurenines and other pathways are being revealed. This review surveys some of these alternative approaches to influence T cell function indirectly via the kynurenine pathway and summarizes the most recent work on the development of compounds acting directly on the kynurenine pathway., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Many invasive micro-organisms produce 'quorum sensor' molecules which regulate colony expansion and may modulate host immune responses. We have examined the ability of Pseudomonas Quorum Sensor (PQS) to influence cytokine expression under conditions of inflammatory stress. The administration of PQS in vivo to mice with collagen-induced arthritis (CIA) increased the severity of disease. Blood and inflamed paws from treated mice had fewer regulatory T cells (Tregs) but normal numbers of Th17 cells. However, PQS (1μM) treatment of antigen-stimulated lymph node cells from collagen-immunised mice in vitro inhibited the differentiation of CD4+IFNγ + cells, with less effect on CD4+IL-17+ cells and no change in CD4+FoxP3 + Tregs. PQS also inhibited T cell activation by anti-CD3/anti-CD28 antibodies. PQS reduced murine macrophage polarisation and inhibited expression of IL1B and IL6 genes in murine macrophages and human THP-1 cells. In human monocyte-derived macrophages, IDO1 gene, protein and enzyme activity were all inhibited by exposure to PQS. TNF gene expression was inhibited in THP-1 cells but not murine macrophages, while LPS-induced TNF protein release was increased by high PQS concentrations. PQS is known to have iron scavenging activity and its suppression of cytokine release was abrogated by iron supplementation. Unexpectedly, PQS decreased the expression of indoleamine-2, 3-dioxygenase genes (IDO1 and IDO2), IDO1 protein expression and enzyme activity in mouse and human macrophages. This is consistent with evidence that IDO1 inhibition or deletion exacerbates arthritis, while kynurenine reduces its severity. It is suggested that the inhibition of IDO1 and cytokine expression may contribute to the quorum sensor and invasive actions of PQS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ogbechi, Huang, Clanchy, Pantazi, Topping, Darlington, Williams and Stone.)

Several serine proteases have been linked to autoimmune disorders and tumour initiation although the mechanisms are not fully understood. Activation of the kynurenine pathway enzyme indoleamine-2,3-dioxygenase (IDO1) modulates cellular activity in the brain, tolerogenesis in the immune system and is a major checkpoint in cancer development. We now report that IDO1 mRNA and IDO1 protein expression (generating kynurenine) are induced in human monocyte-derived macrophages by several chymotryptic serine proteases with direct links to tumorigenesis, including Prostate Specific Antigen (PSA), CD26 (Dipeptidyl-peptidase-4, CD26/DPP-4), High Temperature Requirement protein-A (HtrA), and the bacterial virulence factor subtilisin. These proteases also induce expression of the pro-inflammatory cytokine genes IL1B and IL6 . Other serine proteases tested: bacterial glu-C endopeptidase and mammalian Pro-protein Convertase Subtilase-Kexin-3 (PCSK3, furin), urokinase plasminogen activator (uPA), cathepsin G or neutrophil elastase, did not induce IDO1 , indicating that the reported effects are not a general property of all serine proteases. The results represent a novel mechanism of activating immunosuppressive IDO1 and inducing kynurenine generation which, together with the production of inflammatory cytokines, would contribute to tumour initiation and progression, providing a new target for drug development. In addition, the proteasomal S20 serine protease inhibitor carfilzomib, used in the treatment of myeloma, prevented the induction of IDO1 and cytokine gene expression, potentially contributing to its clinical anti-cancer activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Clanchy, Huang, Ogbechi, Darlington, Williams and Stone.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The importance of the kynurenine pathway in normal immune system function has led to an appreciation of its possible contribution to autoimmune disorders such as rheumatoid arthritis. Indoleamine-2,3-dioxygenase (IDO) activity exerts a protective function, limiting the severity of experimental arthritis, whereas deletion or inhibition exacerbates the symptoms. Other chronic disorder with an inflammatory component, such as atherosclerosis, are also suppressed by IDO activity. It is suggested that this overall anti-inflammatory activity is mediated by a change in the relative production or activity of Th17 and regulatory T cell populations. Kynurenines may play an anti-inflammatory role also in CNS disorders such as Huntington's disease, Alzheimer's disease and multiple sclerosis, in which signs of inflammation and neurodegeneration are involved. The possibility is discussed that in Huntington's disease kynurenines interact with other anti-inflammatory molecules such as Human Lymphocyte Antigen-G which may be relevant in other disorders. Kynurenine involvement may account for the protection afforded to animals with cerebral malaria and trypanosomiasis when they are treated with an inhibitor of kynurenine-3-monoxygenase (KMO). There is some evidence that changes in IL-10 may contribute to this protection and the relationship between kynurenines and IL-10 in arthritis and other inflammatory conditions should be explored. In addition, metabolites of kynurenine downstream of KMO, such as anthranilic acid and 3-hydroxy-anthranilic acid can influence inflammation, and the ratio of these compounds is a valuable biomarker of inflammatory status although the underlying molecular mechanisms of the changes require clarification. Hence it is essential that more effort be expended to identify their sites of action as potential targets for drug development. Finally, we discuss increasing awareness of the epigenetic regulation of IDO, for example by DNA methylation, a phenomenon which may explain differences between individuals in their susceptibility to arthritis and other inflammatory disorders., (Copyright © 2020 Huang, Ogbechi, Clanchy, Williams and Stone.)

Background: The kynurenine pathway of tryptophan oxidation is associated with central nervous system (CNS) inflammatory pathways. Inhibition of this pathway ameliorates CNS inflammation in rodent models of the late (meningoencephalitic) stage of human African trypanosomiasis (HAT). In this study, we evaluate whether the kynurenine pathway is activated in clinical HAT and associated with CNS inflammatory responses., Methods: We measured cerebrospinal fluid (CSF) tryptophan and kynurenine metabolite concentrations in patients infected with Trypanosoma brucei rhodesiense, using liquid chromatography-mass spectrometry., Results: Kynurenine concentration in CSF was increased in both the early and late stages of disease, with a progressive increase in tryptophan oxidation associated with stage progression. Kynurenine pathway activation was associated with increases in neuroinflammatory markers, but there was no clear relationship to neurological symptoms., Conclusions: CNS kynurenine pathway activation occurs during HAT, including cases prior to the current diagnostic cutoff for late-stage infection, providing evidence for early CNS involvement in HAT. Metabolite data demonstrate that the kynurenine-3-monooxygenase and kynurenine aminotransferase branches of the kynurenine pathway are active. The association between tryptophan oxidation and CNS inflammatory responses as measured by CSF interleukin 6 (IL-6) concentration supports a role of kynurenine metabolites in the inflammatory pathogenesis of late-stage HAT., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.)

Research on the neurobiology of the kynurenine pathway has suffered years of relative obscurity because tryptophan degradation, and its involvement in both physiology and major brain diseases, was viewed almost exclusively through the lens of the well-established metabolite serotonin. With increasing recognition that kynurenine and its metabolites can affect and even control a variety of classic neurotransmitter systems directly and indirectly, interest is expanding rapidly. Moreover, kynurenine pathway metabolism itself is modulated in conditions such as infection and stress, which are known to induce major changes in well-being and behaviour, so that kynurenines may be instrumental in the etiology of psychiatric and neurological disorders. It is therefore likely that the near future will not only witness the discovery of additional physiological and pathological roles for brain kynurenines, but also ever-increasing interest in drug development based on these roles. In particular, targeting the kynurenine pathway with new specific agents may make it possible to prevent disease by appropriate pharmacological or genetic manipulations. The following overview focuses on areas of kynurenine research which are either controversial, of major potential therapeutic interest, or just beginning to receive the degree of attention which will clarify their relevance to neurobiology and medicine. It also highlights technical issues so that investigators entering the field, and new research initiatives, are not misdirected by inappropriate experimental approaches or incorrect interpretations at this time of skyrocketing interest in the subject matter. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

To quantify the full range of tryptophan metabolites along the kynurenine pathway, a liquid chromatography - tandem mass spectrometry method was developed and used to analyse brain extracts of rodents treated with the kynurenine-3-mono-oxygenase (KMO) inhibitor Ro61-8048 during pregnancy. There were significant increases in the levels of kynurenine, kynurenic acid, anthranilic acid and 3-hydroxy-kynurenine (3-HK) in the maternal brain after 5 h but not 24 h, while the embryos exhibited high levels of kynurenine, kynurenic acid and anthranilic acid after 5 h which were maintained at 24 h post-treatment. At 24 h there was also a strong trend to an increase in quinolinic acid levels (P = 0.055). No significant changes were observed in any of the other kynurenine metabolites. The results confirm the marked increase in the accumulation of some neuroactive kynurenines when KMO is inhibited, and re-emphasise the potential importance of changes in anthranilic acid. The prolonged duration of metabolite accumulation in the embryo brains indicates a trapping of compounds within the embryonic CNS independently of maternal levels. When brains were examined from young mice heterozygous for the meCP2 gene - a potential model for Rett syndrome - no differences were noted from control mice, suggesting that the proposed roles for kynurenines in autism spectrum disorder are not relevant to Rett syndrome, supporting its recognition as a distinct, independent, condition., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The role of the amino acid tryptophan in the generation of 5-hydroxy-tryptamine (5-HT) has been expanded over the past 30 years with recognition that its oxidation by indoleamine-2,3-dioxygenase (IDO) results in the formation of kynurenine and metabolites which regulate neuronal excitability, psychiatric status, immune cell activity and balance, and probably implantation and the development of embryos. While the amount of work on this kynurenine pathway continues to accelerate, it is important that disagreements about results, differences of interpretation or problems with technical issues are presented openly and discussed thoroughly so that new research is not mis-led in ways that could have been foreseen. In this issue of Clinical Science, Badawy et al. discuss in depth two opposing views of how changes in tryptophan availability or utilisation bring about their effects on cell function. The original concept that local depletion of tryptophan is responsible seems to be less attractive than the view that kynurenine and its metabolites have direct, potent actions on cells. This conclusion not only clarifies our understanding of the importance of tryptophan metabolism to kynurenine but also raises the possibility that the actions of those metabolites could be novel targets for the development of agonists and antagonists with a range of medical implications., (© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.)

Inhibition of the kynurenine pathway of tryptophan metabolism during gestation can lead to changes in synaptic transmission, neuronal morphology and plasticity in the rat hippocampus. This suggests a role for the kynurenine pathway in early brain development, probably caused by kynurenine modulation of N-methyl-d-aspartate (NMDA) glutamate receptors which are activated by the tryptophan metabolite quinolinic acid and blocked by kynurenic acid. We have now examined samples of neocortex and cerebellum of adult animals to assess the effects of a prenatally administered kynurenine-3-monoxygenase inhibitor (Ro61-8048) on protein and mRNA expression, dendritic structure and immuno-histochemistry. No changes were seen in mRNA expression using quantitative real-time polymerase chain reaction. Changes were detected in the expression of several proteins including the GluN2A subunit, unco-ordinated-5H3 (unc5H3), doublecortin, cyclo-oxygenase, sonic hedgehog and Disrupted in schizophrenia-1 (DISC1), although no differences in immunoreactive cell numbers were observed. In the midbrain, dependence receptor expression was also changed. The numbers and lengths of individual dendritic regions were not changed but there were significant increases in the overall complexity values of apical and basal dendritic trees. The data support the hypothesis that constitutive kynurenine metabolism plays a critical role in early, embryonic brain development, although fewer effects are produced in the neocortex and cerebellum than in the hippocampus and the nature of the changes seen are qualitatively different. The significant changes in DISC1 and unc5H3 may be relevant to cerebellar dysfunction and schizophrenia respectively, in which these proteins have been previously implicated., (Copyright © 2014. Published by Elsevier B.V.)

Glutamate receptors for N-methyl-d-aspartate (NMDA) are involved in early brain development. The kynurenine pathway of tryptophan metabolism includes the NMDA receptor agonist quinolinic acid and the antagonist kynurenic acid. We now report that prenatal inhibition of the pathway in rats with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulphonamide (Ro61-8048) produces marked changes in hippocampal neuron morphology, spine density and the immunocytochemical localisation of developmental proteins in the offspring at postnatal day 60. Golgi-Cox silver staining revealed decreased overall numbers and lengths of CA1 basal dendrites and secondary basal dendrites, together with fewer basal dendritic spines and less overall dendritic complexity in the basal arbour. Fewer dendrites and less complexity were also noted in the dentate gyrus granule cells. More neurons containing the nuclear marker NeuN and the developmental protein sonic hedgehog were detected in the CA1 region and dentate gyrus. Staining for doublecortin revealed fewer newly generated granule cells bearing extended dendritic processes. The number of neuron terminals staining for vesicular glutamate transporter (VGLUT)-1 and VGLUT-2 was increased by Ro61-8048, with no change in expression of vesicular GABA transporter or its co-localisation with vesicle-associated membrane protein-1. These data support the view that constitutive kynurenine metabolism normally plays a role in early embryonic brain development, and that interfering with it has profound consequences for neuronal structure and morphology, lasting into adulthood., (© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Activation of the immune system during pregnancy is believed to lead to psychiatric and neurological disorders in the offspring, but the molecular changes responsible are unknown. Polyinosinic:polycytidylic acid (poly(I:C)) is a viral-mimetic double-stranded RNA complex which activates Toll-Like-Receptor-3 and can activate the metabolism of tryptophan through the oxidative kynurenine pathway to compounds that modulate activity of glutamate receptors. The aim was to determine whether prenatal administration of poly(I:C) affects the expression of neurodevelopmental proteins in the offspring and whether such effects were mediated via the kynurenine pathway. Pregnant rats were treated with poly(I:C) during late gestation and the offspring were allowed to develop to postnatal day 21 (P21). Immunoblotting of the brains at P21 showed decreased expression of sonic hedgehog, a key protein in dopaminergic neuronal maturation. Expression of α-synuclein was decreased, while tyrosine hydroxylase was increased. Disrupted in Schizophrenia-1 (DISC-1) and 5-HT2C receptor levels were unaffected, as were the dependence receptors Unc5H1, Unc5H3 and Deleted in Colorectal Cancer (DCC), the inflammation-related transcription factor NFkB and the inducible oxidative enzyme cyclo-oxygenase-2 (COX-2). An examination of embryo brains 5 h after maternal poly(I:C) showed increased expression of GluN2B, with reduced doublecortin and DCC but no change in NFkB. Despite altered protein expression, there were no changes in the kynurenine pathway. The results show that maternal exposure to poly(I:C) alters the expression of proteins in the embryos and offspring which may affect the development of dopaminergic function. The oxidation of tryptophan along the kynurenine pathway is not involved in these effects.

Understanding the neurochemical basis for cognitive function is one of the major goals of neuroscience, with a potential impact on the diagnosis, prevention and treatment of a range of psychiatric and neurological disorders. In this review, the focus will be on a biochemical pathway that remains under-recognized in its implications for brain function, even though it can be responsible for moderating the activity of two neurotransmitters fundamentally involved in cognition - glutamate and acetylcholine. Since this pathway - the kynurenine pathway of tryptophan metabolism - is induced by immunological activation and stress, it also stands in a unique position to mediate the effects of environmental factors on cognition and behaviour. Targeting the pathway for new drug development could, therefore, be of value not only for the treatment of existing psychiatric conditions, but also for preventing the development of cognitive disorders in response to environmental pressures., (© 2013 The British Pharmacological Society.)

Glutamate receptors sensitive to N-methyl-d-aspartate (NMDA) are important in early brain development, influencing cell proliferation and migration, neuritogenesis, axon guidance and synapse formation. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Rats were treated in late gestation with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]-benzene-sulphonamide (Ro61-8048), an inhibitor of kynurenine-3-monoxygenase which diverts kynurenine metabolism to kynurenic acid. Within 5h of drug administration, there was a significant decrease in GluN2A expression and increased GluN2B in the embryo brains, with changes in sonic hedgehog at 24h. When injected dams were allowed to litter normally, the brains of offspring were removed at postnatal day 21 (P21). Recordings of hippocampal field excitatory synaptic potentials (fEPSPs) showed that prenatal exposure to Ro61-8048 increased neuronal excitability and paired-pulse facilitation. Long-term potentiation was also increased, with no change in long-term depression. At this time, levels of GluN2A, GluN2B and postsynaptic density protein PSD-95 were all increased. Among several neurodevelopmental proteins, the expression of sonic hedgehog was increased, but DISC1 and dependence receptors were unaffected, while raised levels of doublecortin and Proliferating Cell Nuclear Antigen (PCNA) suggested increased neurogenesis. The results reveal that inhibiting the kynurenine pathway in utero leads to molecular and functional synaptic changes in the embryos and offspring, indicating that the pathway is active during gestation and plays a significant role in the normal early development of the embryonic and neonatal nervous system., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)

The kynurenine pathway of tryptophan metabolism accounts for most of the tryptophan that is not committed to protein synthesis and includes compounds active in the nervous and immune systems. Kynurenine acts on the aryl hydrocarbon receptor, affecting the metabolism of xenobiotics and promoting carcinogenesis. Quinolinic acid is an agonist at N-methyl-D-aspartate receptors (NMDARs), but is also pro-oxidant, has immunomodulatory actions, and promotes the formation of hyperphosphorylated tau proteins. Kynurenic acid blocks NMDARs and α7-homomeric nicotinic cholinoceptors and is also an agonist at the orphan G-protein-coupled receptor GPR35. 3-Hydroxykynurenine and 3-hydroxyanthranilic acid have pronounced redox activity and regulate T cell function. Cinnabarinic acid can activate metabotropic glutamate receptors. This review highlights 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., (Copyright © 2012. Published by Elsevier Ltd.)

The oxidative pathway for the metabolism of tryptophan along the kynurenine pathway generates quinolinic acid, an agonist at N-methyl-D-aspartate receptors, as well as kynurenic acid which is an antagonist at glutamate and nicotinic receptors. The pathway has become recognized as a key player in the mechanisms of neuronal damage and neurodegenerative disorders. As a result, manipulation of the pathway, so that the balance between the levels of components of the pathway can be modified, has become an attractive target for the development of pharmacological agents with the potential to treat those disorders. This review summarizes some of the relevant background information on the pathway itself before identifying some of the chemical strategies for its modification, with examples of their successful application in animal models of infection, stroke, traumatic brain damage, cerebral malaria and cerebral trypanosomiasis., (© 2012 The Authors Journal compilation © 2012 FEBS.)

Several components of the kynurenine pathway of tryptophan metabolism are now recognised to have actions of profound biological importance. These include the ability to modulate the activation of glutamate and nicotinic receptors, to modify the responsiveness of the immune system to inflammation and infection, and to modify the generation and removal of reactive oxygen species. As each of these factors is being recognised increasingly as contributing to major disorders of the central nervous system (CNS), so the potentially fundamental role of the kynurenine pathway in those disorders is presenting a valuable target both for understanding the progress of those disorders and for developing potential drug treatments. This review will summarise some of the evidence for an important contribution of the kynurenines to Huntington's disease and to stroke damage in the CNS. Together with preliminary evidence from a study of kynurenine metabolites after major surgery, an important conclusion is that kynurenine pathway activation closely reflects cognitive function, and may play a significant role in cognitive ability.

Cardiac surgery involving extra-corporeal circulation can lead to cognitive dysfunction. As such surgery is associated with signs of inflammation and pro-inflammatory mediators activate tryptophan oxidation to neuroactive kynurenines which modulate NMDA receptor function and oxidative stress, we have measured blood concentrations of kynurenines and inflammatory markers in 28 patients undergoing coronary arterial graft surgery and, for comparison, 28 patients undergoing non-bypass thoracic surgery. A battery of cognitive tests was completed before and after the operations. The results show increased levels of tryptophan with decreased levels of kynurenine, anthranilic acid and 3-hydroxyanthranilic acid associated with bypass, and a later increase in kynurenic acid. Levels of neopterin and lipid peroxidation products rose after surgery in non-bypass patients whereas tumour necrosis factor-α and S100B levels increased after bypass. Changes of neopterin levels were greater after non-bypass surgery. Cognitive testing showed that the levels of tryptophan, kynurenine, kynurenic acid and the kynurenine/tryptophan ratio, correlated with aspects of post-surgery cognitive function, and were significant predictors of cognitive performance in tasks sensitive to frontal executive function and memory. Thus, anaesthesia and major surgery are associated with inflammatory changes and alterations in tryptophan oxidative metabolism which predict, and may play a role in, post-surgical cognitive function., (© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)

There is substantial evidence that abnormal concentrations of oxidised tryptophan metabolites, produced via the kynurenine pathway, contribute to progressive neurodegeneration in Huntington's disease. We have now examined the blood levels of these metabolites in patients at different stages of Huntington's disease, assessed both in terms of clinical disease severity and numbers of CAG repeats. Close relatives of the patients were included in the study as well as unrelated healthy controls. Levels of lipid peroxidation products, the pro-inflammatory cytokine interleukin (IL)-23 and the soluble human leucocyte antigen-G (sHLA-G) were also measured. There were lower levels of tryptophan and a higher kynurenine : tryptophan ratio, indicating activation of indoleamine-2,3-dioxygenase, in the most severely affected group of patients, with increased levels of IL-23 and sHLA-G. Marked correlations were noted between IL-23 and the patient severity group, anthranilic acid levels and the number of CAG repeats, and between anthranilic acid and IL-23, supporting our previous evidence of a relationship between anthranilic acid and inflammatory status. Tryptophan was negatively correlated with symptom severity and number of CAG repeats, and positively correlated with sHLA-G. The results support the proposal that tryptophan metabolism along the kynurenine pathway in Huntington's disease is related to the degree of genetic abnormality, to clinical disease severity and to aspects of immunopathogenesis.

Human African trypanosomiasis, or sleeping sickness, is caused by the protozoan parasites Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiense, and is a major cause of systemic and neurological disability throughout sub-Saharan Africa. Following early-stage disease, the trypanosomes cross the blood-brain barrier to invade the central nervous system leading to the encephalitic, or late stage, infection. Treatment of human African trypanosomiasis currently relies on a limited number of highly toxic drugs, but untreated, is invariably fatal. Melarsoprol, a trivalent arsenical, is the only drug that can be used to cure both forms of the infection once the central nervous system has become involved, but unfortunately, this drug induces an extremely severe post-treatment reactive encephalopathy (PTRE) in up to 10% of treated patients, half of whom die from this complication. Since it is unlikely that any new and less toxic drug will be developed for treatment of human African trypanosomiasis in the near future, increasing attention is now being focussed on the potential use of existing compounds, either alone or in combination chemotherapy, for improved efficacy and safety. The kynurenine pathway is the major pathway in the metabolism of tryptophan. A number of the catabolites produced along this pathway show neurotoxic or neuroprotective activities, and their role in the generation of central nervous system inflammation is well documented. In the current study, Ro-61-8048, a high affinity kynurenine-3-monooxygenase inhibitor, was used to determine the effect of manipulating the kynurenine pathway in a highly reproducible mouse model of human African trypanosomiasis. It was found that Ro-61-8048 treatment had no significant effect (P = 0.4445) on the severity of the neuroinflammatory pathology in mice during the early central nervous system stage of the disease when only a low level of inflammation was present. However, a significant (P = 0.0284) reduction in the severity of the neuroinflammatory response was detected when the inhibitor was administered in animals exhibiting the more severe, late central nervous system stage, of the infection. In vitro assays showed that Ro-61-8048 had no direct effect on trypanosome proliferation suggesting that the anti-inflammatory action is due to a direct effect of the inhibitor on the host cells and not a secondary response to parasite destruction. These findings demonstrate that kynurenine pathway catabolites are involved in the generation of the more severe inflammatory reaction associated with the late central nervous system stages of the disease and suggest that Ro-61-8048 or a similar drug may prove to be beneficial in preventing or ameliorating the PTRE when administered as an adjunct to conventional trypanocidal chemotherapy.

1. Depression could result from changes in tryptophan availability caused by activation of the kynurenine pathway as a result of inflammation. In the present study, we examined patients newly diagnosed with depression to determine whether kynurenines and related factors change in parallel with improvements in mood. 2. Concentrations of 5-hydroxytryptamine (5-HT; serotonin), 5-hydroxyindoleacetic acid (5-HIAA), oxidized tryptophan metabolites, brain-derived neurotrophic factor (BDNF) and inflammatory mediators (interleukin (IL)-2, C-reactive protein (CRP), neopterin) were measured in peripheral blood during an 18 week period of treatment with fluoxetine, fluoxetine plus tri-iodothyronine (T(3)) or psychiatric counselling. 3. The results showed significant improvements in mood, with reduced 5-HT concentrations in patients given fluoxetine and a rise in plasma tryptophan in patients given counselling or fluoxetine and T(3). The addition of T(3) to the fluoxetine regimen appeared to slow recovery from depression, although the use of T(3) was associated with a fall in thyroxine concentrations. Changes in 5-HT concentrations did not correlate with psychiatric scores and were seen only in drug-treated groups, not those given counselling. There were no associated changes in absolute concentrations of kynurenines, BDNF, CRP, neopterin or IL-2. With fluoxetine treatment, there were correlations between the concentrations of kynurenine metabolites and the psychiatric rating scores, whereas no correlations were found with BDNF or inflammatory markers. 4. It is concluded that depression scores are largely independent of inflammatory status, but kynurenine metabolism may be related to the degree of depression after fluoxetine treatment.

Aim: Since melatonin is antioxidant and has some anti-inflammatory actions, we have tested it as adjunctive treatment in patients with rheumatoid arthritis, to determine whether it can improve patients' symptoms., Methods: A total of 75 patients were allocated randomly to receive melatonin 10 mg at night in addition to ongoing medication, or a placebo of identical appearance. Monthly blood samples were taken and disease severity assessed over 6 months, plasma being analysed for inflammatory indicators [C-reactive protein, erythrocyte sedimentation rate (ESR), neopterin], proinflammatory cytokines [interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF)-alpha], lipid peroxidation products and the kynurenine pathway metabolites of tryptophan., Results: An increase of ESR (two-way anova F((1,127)) = 5.24, P = 0.024) and neopterin concentrations (F((1,136)) = 4.64, P = 0.033) was observed in treated patients compared with controls, reflected also in a significant trend for both to decline in placebo-treated patients (P = 0.022), but not the melatonin-treated group. Peroxidation products showed a significant trend to decrease in placebo- but not melatonin-treated patients. These results suggest a proinflammatory action, but there were no significant effects of melatonin treatment on clinical assessments of patient symptoms or the concentrations of three proinflammatory cytokines, IL-1beta, IL-6 and TNF-alpha. Melatonin significantly increased plasma kynurenine concentrations (F((1,124)) = 4.24, P = 0.041), again suggesting proinflammatory activity., Conclusion: A daily dose of 10 mg melatonin shows a slowly developing antioxidant profile in patients with arthritis and increases the concentrations of some inflammatory indicators, but these effects are not associated with any change of proinflammatory cytokine concentrations or clinical symptoms.

1. Metabolism of tryptophan along the oxidative pathway via kynurenine results in the production of quinolinic acid and kynurenic acid, which can act on glutamate receptors in peripheral tissues. We have now measured the concentrations of kynurenine pathway metabolites in the plasma of patients with osteoporosis before treatment with drugs, throughout and after 2 years of treatment with the drugs raloxifene or etidronate. Oxidative stress was assessed by measuring levels of the lipid peroxidation products malondialdehyde and 4-hydroxynonenal. Kynurenines were analysed by HPLC. Bone density was measured using dual-energy X-ray absorptiometry scans. 2. Patients with osteoporosis showed significantly lower baseline levels of 3-hydroxyanthranilic acid compared with healthy controls, but significantly higher levels of anthranilic acid and lipid peroxidation products. After 2 years treatment with etidronate and calcium, we observed significant therapeutic responses quantified by bone densitometric scanning. Significant improvements were not seen in patients treated with raloxifene. 3. In parallel, the levels of 3-hydroxyanthranilic acid, anthranilic acid and lipid peroxidation products were restored to control values by both drug treatments studied and tryptophan levels were increased significantly compared with baseline values. 4. The results suggest that tryptophan metabolism is altered in osteoporosis in a manner that could contribute to the oxidative stress and, thus, to progress of the disease. The oxidative metabolism of tryptophan (the kynurenine pathway) could represent a novel target for the development of new drugs for the treatment of osteoporosis. In addition, we noted that etidronate is a more effective drug than raloxifene, but that the simultaneous use of non-steroidal anti-inflammatory drugs may reduce the efficacy of etidronate.

C57BL/6J mice infected with Plasmodium berghei ANKA develop neurological dysfunction and die within 7 days of infection. We show that treatment of infected mice with a kynurenine-3-hydroxylase inhibitor prevents them from developing neurological symptoms and extends their life span threefold until severe anemia develops.

Tryptophan is metabolised primarily along the kynurenine pathway, of which two components are now known to have marked effects on neurons in the central nervous system. Quinolinic acid is an agonist at the population of glutamate receptors which are sensitive to N-methyl-D-aspartate (NMDA), and kynurenic acid is an antagonist at several glutamate receptors. Consequently quinolinic acid can act as a neurotoxin while kynurenic acid is neuroprotectant. A third kynurenine, 3-hydroxykynurenine, can generate free radicals and contribute to, or exacerbate, neuronal damage. Changes in the absolute or relative concentrations of these kynurenines have been implicated in a variety of central nervous system disorders such as the AIDS-dementia complex and Huntington's disease, raising the possibility that interference with their actions or synthesis could lead to new forms of pharmacotherapy for these conditions.

Kynurenines are formed as part of the tryptophan metabolism and are known to exhibit pro- and anti-oxidant activities in vitro. The mapping of these biological redox-systems and identification of potential in vivo targets are therefore of great interest in cellular physiology. Here the redox-behavior of different kynurenines and anthranilic acids is evaluated electrochemically and compared to that of simple model compounds. Electrochemical results are correlated with the activity of these compounds in redox-bioassays where 3-hydroxyanthranilic acid and 3-hydroxykynurenine have significant redox-activity. The specific electrochemical redox-behavior of these two compounds, indicating a particular redox-mechanism involving the hydroxyl group, can be used to rationalize these findings. The results indicate that tryptophan metabolites can undergo a range of complex redox-reactions in vivo whose precise nature critically depends on structural details. As a consequence, some of the kynurenines have the potential to contribute to neuronal damage in brain disorders and stroke.

The kynurenine pathway from tryptophan generates compounds which can act on glutamate receptors in peripheral tissues or modulate free radical activity. We have measured the concentrations of several of these compounds in the plasma of patients with rheumatoid arthritis (RA) and osteoporosis (OP) before treatment with drugs and then at monthly intervals for 6 months during treatment. Kynurenine analysis was performed by HPLC. Compared with healthy controls, RA patients showed significantly decreased baseline levels of tryptophan, 3-hydroxykynurenine and 3-hydroxyanthranilic acid and increased levels of kynurenine and xanthurenic acid, while kynurenic acid concentrations were normal. Different results were recorded from patients with OP with only a significant reduction in tryptophan and 3-hydroxyanthranilic acid when compared with healthy controls. During 6 months of treating the RA patients with prednisolone or methotrexate, and the OP patients with raloxifene or etidronate and calcium there were significant therapeutic responses and a significant trend towards a reduction in levels of neopterin in RA patients receiving methotrexate but no changes in the profiles of tryptophan metabolites. The results are consistent with the induction of indoleamine-2,3-dioxygenase (IDO) in both RA and OP but with far greater activation of the pathway in the much more inflammatory condition, i.e. RA. It is concluded that there are changes in the kynurenine pathway, which may modify the activation of tissue glutamate receptors, in RA and OP, but that these are not affected by the drug treatments studied.

The factors affecting gut activity in inflammatory bowel disease are unclear, but purines and kynurenines may be involved in the regulation of neuronal activity and therefore gut motility and secretion. We have measured the serum levels of these compounds in patients and in sex- and age-matched controls. Purines and kynurenines were analysed using HPLC. The levels of tryptophan and its metabolites 3-hydroxykynurenine, 3-hydroxyanthranilic acid and xanthurenic acid were unchanged in all patients. However, the levels of kynurenine and kynurenic acid were significantly elevated in patients with inflammatory bowel disease when compared to control subjects. There were no significant differences between patients and controls for any of the purines analysed or for neopterin. In the inflammatory bowel disease patients serum lipid peroxidation products were significantly elevated when compared to control subjects, suggesting the presence of increased oxidative stress consistent with inflammatory activity. The elevated level of kynurenic acid may represent either a compensatory response to elevated activation of enteric neurones, or a primary abnormality, which induces a compensatory increase in gut activity, but may indicate a role for kynurenine modulation of glutamate receptors in the symptoms of inflammatory bowel disease.

The kynurenine metabolites of tryptophan may be involved in the regulation of neuronal activity and thus gut motility and secretion. We have now performed a pilot study to measure serum concentrations of purines and kynurenines in patients with mild inflammatory bowel disease, as well as in sex- and age-matched control subjects. For some analyses, the patients were subdivided into subgroups of those with Crohn's disease and those with ulcerative colitis. The analyses indicated an increased activity in one branch of the kynurenine pathway. While there was no demonstrable difference in neopterin levels in either of the patient groups compared with controls, indicating that the disorders were in an inactive quiescent phase, both groups showed significantly higher levels of lipid peroxidation products. This suggests the presence of increased oxidative stress even during relative disease inactivity. The increased level of kynurenic acid may represent either a compensatory response to elevated activation of enteric neurones or a primary abnormality which induces a compensatory increase in gut activity. In either case, the data may indicate a role for kynurenine modulation of glutamate receptors in the symptoms of inflammatory bowel disease., (Copyright 2002 National Science Council, ROC and S. Karger AG, Basel)

The kynurenine pathway is the main pathway for tryptophan metabolism. It generates compounds that can modulate activity at glutamate receptors and possibly nicotinic receptors, in addition to some as-yet-unidentified sites. The pathway is in a unique position to regulate other aspects of the metabolism of tryptophan to neuroactive compounds, and also seems to be a key factor in the communication between the nervous and immune systems. It also has potentially important roles in the regulation of cell proliferation and tissue function in the periphery. As a result, the pathway presents a multitude of potential sites for drug discovery in neuroscience, oncology and visceral pathology.

It has been unequivocally established that kynurenic acid has a number of actions in a variety of cells and tissues, raising, in principle, the possibility of targeting its generation, metabolism or sites of action to manipulate those effects to a beneficial therapeutic end. However, many basic aspects of the biology of kynurenic acid remain unclear, potentially leading to some confusion and misinterpretations of data. They include questions of the source, generation, targets, enzyme expression, endogenous concentrations and sites of action. This essay is intended to raise and discuss many of these aspects as a source of reference for more balanced discussion. Those issues are followed by examples of situations in which modulating and correcting kynurenic acid production or activity could bring significant therapeutic benefit, including neurological and psychiatric conditions, inflammatory diseases and cell protection. More information is required to obtain a clear overall view of the pharmacological environment relevant to kynurenic acid, especially with respect to the active concentrations of kynurenine metabolites in vivo and changed levels in disease. The data and ideas presented here should permit a greater confidence in appreciating the sites of action and interaction of kynurenic acid under different local conditions and pathologies, enhancing our understanding of kynurenic acid itself and the many clinical conditions in which manipulating its pharmacology could be of clinical value. [ABSTRACT FROM AUTHOR]

Simple Summary: There is clear evidence that inflammation can contribute to the development of cancers, but the underlying mechanisms are not fully understood. This review focuses on metabolites of the amino acid tryptophan, especially kynurenine and related compounds, which are produced in response to inflammation and which have been implicated in cancer progression. Unfortunately, one drug that inhibits the generation of these compounds, epacadostat, has not been very successful. The review explains the actions of each of the relevant tryptophan metabolites and discusses how they interact with other compounds and biochemical pathways known to affect cancer formation. The objective is to demonstrate that the kynurenine pathway could be targeted to affect those interacting pathways indirectly and that those alternative routes could represent a means of modifying tryptophan metabolism indirectly. In either case, the range of possible targets for drugs that inhibit the link between inflammation and cancer would be expanded. The mechanisms underlying a relationship between inflammation and cancer are unclear, but much emphasis has been placed on the role of tryptophan metabolism to kynurenine and downstream metabolites, as these make a substantial contribution to the regulation of immune tolerance and susceptibility to cancer. The proposed link is supported by the induction of tryptophan metabolism by indoleamine-2,3-dioxygenase (IDO) or tryptophan-2,3-dioxygenase (TDO), in response to injury, infection or stress. This review will summarize the kynurenine pathway and will then focus on the bi-directional interactions with other transduction pathways and cancer-related factors. The kynurenine pathway can interact with and modify activity in many other transduction systems, potentially generating an extended web of effects other than the direct effects of kynurenine and its metabolites. Conversely, the pharmacological targeting of those other systems could greatly enhance the efficacy of changes in the kynurenine pathway. Indeed, manipulating those interacting pathways could affect inflammatory status and tumor development indirectly via the kynurenine pathway, while pharmacological modulation of the kynurenine pathway could indirectly influence anti-cancer protection. While current efforts are progressing to account for the failure of selective IDO1 inhibitors to inhibit tumor growth and to devise means of circumventing the issue, it is clear that there are wider factors involving the relationship between kynurenines and cancer that merit detailed consideration as alternative drug targets. [ABSTRACT FROM AUTHOR]

Two of the molecular families closely associated with mediating communication between the brain and immune system are cytokines and the kynurenine metabolites of tryptophan. Both groups regulate neuron and glial activity in the central nervous system (CNS) and leukocyte function in the immune system, although neither group alone completely explains neuroimmune function, disease occurrence or severity. This essay suggests that the two families perform complementary functions generating an integrated network. The kynurenine pathway determines overall neuronal excitability and plasticity by modulating glutamate receptors and GPR35 activity across the CNS, and regulates general features of immune cell status, surveillance and tolerance which often involves the Aryl Hydrocarbon Receptor (AHR). Equally, cytokines and chemokines define and regulate specific populations of neurons, glia or immune system leukocytes, generating more specific responses within restricted CNS regions or leukocyte populations. In addition, as there is a much larger variety of these compounds, their homing properties enable the superimposition of dynamic variations of cell activity upon local, spatially limited, cell populations. This would in principle allow the targeting of potential treatments to restricted regions of the CNS. The proposed synergistic interface of 'tonic' kynurenine pathway affecting baseline activity and the superimposed 'phasic' cytokine system would constitute an integrated network explaining some features of neuroimmune communication. The concept would broaden the scope for the development of new treatments for disorders involving both the CNS and immune systems, with safer and more effective agents targeted to specific CNS regions. [ABSTRACT FROM AUTHOR]

As a major metabolite of kynurenine in the oxidative metabolism of tryptophan, kynurenic acid is of considerable biological and clinical importance as an endogenous antagonist of glutamate in the central nervous system. It is most active as an antagonist at receptors sensitive to N‐methyl‐D‐aspartate (NMDA) which regulate neuronal excitability and plasticity, brain development and behaviour. It is also thought to play a causative role in hypo‐glutamatergic conditions such as schizophrenia, and a protective role in several neurodegenerative disorders, notably Huntington's disease. An additional hypothesis, that kynurenic acid could block nicotinic receptors for acetylcholine in the central nervous system has been proposed as an alternative mechanism of action of kynurenate. However, the evidence for this alternative mechanism is highly controversial, partly because at least eight earlier studies concluded that kynurenic acid blocked NMDA receptors but not nicotinic receptors and five subsequent, independent studies designed to repeat the results have failed to do so. Many studies considered to support the alternative 'nicotinic' hypothesis have been based on the use of analogs of kynurenate such as 7‐chloro‐kynurenic acid, or putatively nicotinic modulators such as galantamine, but a detailed analysis of the pharmacology of these compounds suggests that the results have often been misinterpreted, especially since the pharmacology of galantamine itself has been disputed. This review examines the evidence in detail, with the conclusion that there is no confirmed, reliable evidence for an antagonist activity of kynurenic acid at nicotinic receptors. Therefore, since there is overwhelming evidence for kynurenate acting at ionotropic glutamate receptors, especially NMDAR glutamate and glycine sites, with some activity at GPR35 sites and Aryl Hydrocarbon Receptors, results with kynurenic acid should be interpreted only in terms of these confirmed sites of action. [ABSTRACT FROM AUTHOR]

Of the major components of the kynurenine pathway for the oxidative metabolism of tryptophan, most attention has focussed on the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid, and the glutamate receptor blocker kynurenic acid. However, there is increasing evidence that the redox-active compound 3-hydroxyanthranilic acid may also have potent actions on cell function in the nervous and immune systems, and recent clinical data show marked changes in the levels of this compound, associated with changes in anthranilic acid levels, in patients with a range of neurological and other disorders including osteoporosis, chronic brain injury, Huntington's disease, coronary heart disease, thoracic disease, stroke and depression. In most cases, there is a decrease in 3-hydroxyanthranilic acid levels and an increase in anthranilic acid levels. In this paper, we summarise the range of data obtained to date, and hypothesise that the levels of 3-hydroxyanthranilic acid or the ratio of 3-hydroxyanthranilic acid to anthranilic acid levels, may contribute to disorders with an inflammatory component, and may represent a novel marker for the assessment of inflammation and its progression. Data are presented which suggest that the ratio between these two compounds is not a simple determinant of neuronal viability. Finally, a hypothesis is presented to account for the development of the observed changes in 3-hydroxyanthranilic acid and anthranilate levels in inflammation and it is suggested that the change of the 3HAA:AA ratio, particularly in the brain, could possibly be a protective response to limit primary and secondary damage. [ABSTRACT FROM AUTHOR]

The essential amino acid tryptophan is primarily metabolised through the kynurenine pathway, some components of which may be neurotoxic. We have now examined the potential toxicity of several kynurenine metabolites in relation to the generation of oxidative stress and activation of cell death signalling pathways in cultured cerebellar granule neurons. 3-Hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HAA) and 5-hydroxyanthranilic acid (5HAA) induced cell death which increased with exposure time and compound concentration. The neurotoxic effects of 3HK, 3HAA and 5HAA were prevented by catalase, but not by superoxide dismutase. In addition, Western blot analysis demonstrated p38 activation due to 3HK or 5HAA treatment, although caspase-3 activation was not evident in either case. The results indicate that kynurenine metabolites can be neurotoxic via a caspase-3 independent mechanism, and that the minor metabolite 5HAA is as potent a toxin as the better documented compounds 3HK and 3HAA. [ABSTRACT FROM AUTHOR]

Human African trypanosomiasis, or sleeping sickness, is caused by the protozoan parasites Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiense, and is a major cause of systemic and neurological disability throughout sub-Saharan Africa. Following early-stage disease, the trypanosomes cross the blood–brain barrier to invade the central nervous system leading to the encephalitic, or late stage, infection. Treatment of human African trypanosomiasis currently relies on a limited number of highly toxic drugs, but untreated, is invariably fatal. Melarsoprol, a trivalent arsenical, is the only drug that can be used to cure both forms of the infection once the central nervous system has become involved, but unfortunately, this drug induces an extremely severe post-treatment reactive encephalopathy (PTRE) in up to 10% of treated patients, half of whom die from this complication. Since it is unlikely that any new and less toxic drug will be developed for treatment of human African trypanosomiasis in the near future, increasing attention is now being focussed on the potential use of existing compounds, either alone or in combination chemotherapy, for improved efficacy and safety. The kynurenine pathway is the major pathway in the metabolism of tryptophan. A number of the catabolites produced along this pathway show neurotoxic or neuroprotective activities, and their role in the generation of central nervous system inflammation is well documented. In the current study, Ro-61-8048, a high affinity kynurenine-3-monooxygenase inhibitor, was used to determine the effect of manipulating the kynurenine pathway in a highly reproducible mouse model of human African trypanosomiasis. It was found that Ro-61-8048 treatment had no significant effect (P = 0.4445) on the severity of the neuroinflammatory pathology in mice during the early central nervous system stage of the disease when only a low level of inflammation was present. However, a significant (P = 0.0284) reduction in the severity of the neuroinflammatory response was detected when the inhibitor was administered in animals exhibiting the more severe, late central nervous system stage, of the infection. In vitro assays showed that Ro-61-8048 had no direct effect on trypanosome proliferation suggesting that the anti-inflammatory action is due to a direct effect of the inhibitor on the host cells and not a secondary response to parasite destruction. These findings demonstrate that kynurenine pathway catabolites are involved in the generation of the more severe inflammatory reaction associated with the late central nervous system stages of the disease and suggest that Ro-61-8048 or a similar drug may prove to be beneficial in preventing or ameliorating the PTRE when administered as an adjunct to conventional trypanocidal chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: The kynurenine pathway of tryptophan oxidative metabolism plays a major role in the nervous and immune systems and has been implicated in a range of disease states. Much of the interest in the pathway has been centred around the role of quinolinic acid as an agonist at glutamate receptors sensitive to N-methyl-d-aspartate (NMDA) and kynurenic acid which blocks all the ionotropic glutamate receptors. In addition, it is clear that the pathway is important in modulating the level of oxidative stress in tissues, partly via the activation of blockade of NMDA receptors, but also via the generation of redox active compounds such as 3-hydroxykynurenine and 3-hydroxyanthranilic acid. Pharmacological interference with this pathway therefore presents a route for reducing oxidative tissue damage at several different metabolic steps, providing a valuable potential therapeutic target for new drug development. [Copyright &y& Elsevier]

The tryptophan metabolite kynurenic acid can block glutamate at ionotropic receptors, but recent evidence suggests a more potent antagonistic action at α7 nicotinic receptors for acetylcholine on cultured neurons. The present study examines activity of kynurenic acid at those nicotinic receptors, which mediate cholinergic neurotransmission onto interneurons in the rat hippocampus. Intracellular recordings were made from pyramidal cells and interneurons in the presence of atropine, bicuculline methobromide, (3-aminopropyl)(diethoxymethyl)-phosphinic acid [CGP35348, to block γ-aminobutyric acid (GABA)B receptors] and 3-tropanyl-3,5-dichlorobenzoate (MDL 72222, to block 5-HT3 receptors). In the added presence of glutamate antagonists 2-amino-5-phosphono-pentanoic acid and 6-cyano-7-nitroquinoxaline-2,3-dione, interneurons exhibited a residual excitatory postsynaptic potential (EPSP) that could be blocked by the nicotinic α7 receptor blocker methyl-lycaconitine, but not by dihydro-β-erythroidine which blocks α4β2 receptors. Kynurenic acid reduced the amplitude of these EPSPs with an EC50 of 136 µm. The amplitudes of nicotinic spontaneous miniature EPSPs were also reduced by methyl-lycaconitine and kynurenic acid. The results show that kynurenic acid is more potent in blocking nicotinic EPSPs compared with the full, glutamate-mediated EPSPs, but it was substantially less potent than has been reported in cultures, possibly because of differences in the accessibility of synaptic and extrasynaptic receptors. It is suggested that blockade of nicotinic synaptic transmission may be relevant to the actions of kynurenic acid in the hippocampus, but that in the intact brain this activity is likely to be comparable in importance to the blockade of glutamate-mediated transmission. [ABSTRACT FROM AUTHOR]

The overactivation of glutamate receptors is a major cause of Ca2+ overload in cells, potentially leading to cell damage and death. There is an abundance of agents and mechanisms by which glutamate receptor activation can be prevented or modulated in order to control these effects. They include the well-established, competitive and non-competitive antagonists at the N-methyl-d-aspartate (NMDA) receptors and modulators of desensitisation of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors. More recently, it has emerged that some compounds can act selectively at different subunits of glutamate receptors, allowing a differential blockade of subtypes. It is also becoming clear that a number of endogenous compounds, including purines, can modify glutamate receptor sensitivity. The kynurenine pathway is an alternative but distinct pathway to the generation of glutamate receptor ligands. The products of tryptophan metabolism via the kynurenine pathway include both quinolinic acid, a selective agonist at NMDA receptors, and kynurenic acid, an antagonist at several glutamate receptor subtypes. The levels of these metabolites change as a result of the activation of inflammatory processes and immune-competent cells, and may have a significant impact on Ca2+ fluxes and neuronal damage. Drugs which target some of these various sites and processes, or which change the balance between the excitotoxin quinolinic acid and the neuroprotective kynurenic acid, could also have potential as neuroprotective drugs. [Copyright &y& Elsevier]

Discusses the development of glutamate receptor antagonists from kynurenic acid and the range of their potential uses in neurology and psychiatry. Compounds that are relevant to neurodegeneration; Therapeutic indications and trials of kynurenic acid analogues; Conclusion.

The IDO/kynurenine pathway is now established as a major regulator of immune system function. The initial enzyme, indoleamine 2,3-dioxygenase (IDO1) is induced by IFNγ, while tryptophan-2,3-dioxygenase (TDO) is induced by corticosteroids. The pathway is therefore positioned to mediate the effects of systemic inflammation or stress-induced steroids on tissue function and its expression increases with age. Disorders of the musculoskeletal system are a common feature of ageing and many of these conditions are characterized by an inflammatory state. In inflammatory arthritis and related disorders, kynurenine protects against the development of disease, while inhibition or deletion of IDO1 increases its severity. The long-term regulation of autoimmune disorders may be influenced by the epigenetic modulation of kynurenine pathway genes, with recent data suggesting that methylation of IDO may be involved. Osteoporosis is also associated with abnormalities of the kynurenine pathway, reflected in an inversion of the ratio between blood levels of the metabolites anthranilic acid and 3-hydroxy-anthranilic acid. This review discusses evidence to date on the role of the IDO/kynurenine pathway and the highly prevalent age-related disorders of osteoporosis and rheumatoid arthritis and identifies key areas that require further research. [ABSTRACT FROM AUTHOR]