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Kynurenine Pathway Metabolites in Humans: Disease and Healthy States

Yiquan Chen, Gilles J. Guillemin

International Journal of Tryptophan Research · 2009 · Review

doi:10.4137/ijtr.s2097

Abstract

Tryptophan is an essential amino acid that can be metabolised through different pathways, a major route being the kynurenine pathway. The first enzyme of the pathway, indoleamine-2,3-dioxygenase, is strongly stimulated by inflammatory molecules, particularly interferon gamma. Thus, the kynurenine pathway is often systematically up-regulated when the immune response is activated. The biological significance is that 1) the depletion of tryptophan and generation of kynurenines play a key modulatory role in the immune response; and 2) some of the kynurenines, such as quinolinic acid, 3-hydroxykynurenine and kynurenic acid, are neuroactive. The kynurenine pathway has been demonstrated to be involved in many diseases and disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, AIDS dementia complex, malaria, cancer, depression and schizophrenia, where imbalances in tryptophan and kynurenines have been found. This review compiles most of these studies and provides an overview of how the kynurenine pathway might be contributing to disease development, and the concentrations of tryptophan and kynurenines in the serum, cerebrospinal fluid and brain tissues in control and patient subjects.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Tryptophan is one of the 9 essential amino acids that the human body is incapable of synthesizing and thus, has to be obtained through external sources. Once absorbed by the body, tryptophan travels around the periphery circulation either bound to albumin or in free form, the two states existing in equilibrium, with the former accounting for up to 90%. However, tryptophan can only be transported across the blood brain barrier in its free form by the competitive and non-specific L-type amino acid transporter. Once in the central nervous system (CNS), tryptophan acts as a precursor to various metabolic pathways. This versatility results in different end-products, such as protein, serotonin and kynurenines. In both the peripheral and central systems, the kynurenine pathway represents a major route for the metabolism of tryptophan.

Following the kynurenine pathway (Fig. 1), tryptophan is oxidized by cleavage of the indole-ring, initiated either by tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO-1) or IDO-2, a newly discovered IDO related enzyme.– TDO resides primarily in the liver and is induced by tryptophan or corticosteroids. IDO-1, on the other hand, is the predominant enzyme extra-hepatically and can be found in numerous cells, including macrophages, microglia, neurons and astrocytes.– It is up-regulated by certain cytokines and inflammatory molecules, such as lipopolysaccharides, amyloid peptides and human immunodeficiency virus (HIV) proteins,,, but its most potent stimulant is interferon gamma (IFN-γ)., IFN-γ is able to induce both the gene expression and enzymatic activity of IDO-1., Recently, an IDO related enzyme, IDO-2, was identified., The encoding genes for IDO-1 and IDO-2 are located next to each other and IDO-2 possesses similar structural and enzymatic activities as IDO-1. However, IDO-2 differs in its expression pattern and signalling pathway and is preferentially inhibited by D-1-methyl-tryptophan.,

As tryptophan proceeds along the kynurenine pathway to achieve the final product, nicotinamide adenosine dinucleotide (NAD), kynurenine is the first stable intermediate formed. Subsequently, several neuroactive intermediates are generated. These comprise the free-radical generator, 3-hydroxyanthranilic acid, the excitotoxin and N-methyl-D-aspartic acid (NMDA) receptor agonist, quinolinic acid, the NMDA antagonist, kynurenic acid, and the neuroprotectant, picolinic acid.

During an immune response, the release of IFN-γ by activated T cells and leukocytes leads to an accelerated and sustained degradation of tryptophan. This significance was first speculated to be a defence mechanism that starved tumour cells, pathogens and parasites of tryptophan., However, with the discovery that IDO-1 activity was necessary for the preservation of allogenic fetuses in mice, further in vitro research found that tryptophan depletion had an anti-proliferative and apoptotic effect on T cells.– In particular, the general control non-derepressible-2 (GCN2) kinase was identified as a key mediator in IDO-1 induced tryptophan depletion immunosuppression. The activation of GCN2 triggers a stress-response program that can result in cell-cycle arrest, differentiation, adaptation or apoptosis.– Furthermore, some of the kynurenines, such as quinolinic acid and 3-hydroxyanthranilic acid, can also effectively suppress T cell proliferation. This inhibition appears to selectively target immune cells undergoing activation and these kynurenines may act in concert to produce an additive effect. Lastly, the production of the excitotoxin quinolinic acid is often significantly increased following inflammation and resulting immune activation.

To date, the kynurenine pathway has been implicated in a variety of diseases and disorders, including acquired immune deficiency syndrome (AIDS) dementia complex, Alzheimer’s disease (AD), schizophrenia, Huntington’s disease, amyotrophic lateral sclerosis (ALS) and neoplasia,– and numerous studies have measured the levels of tryptophan and kynurenines under those conditions. Significant imbalances in tryptophan and its metabolites were frequently observed, which when brought back within normal ranges, often resulted in alleviation of symptoms. This review brings together most of these studies to provide a better idea of the expected differences in tryptophan and kynurenine levels in the serum, cerebrospinal fluid (CSF) and brain between disease and healthy states.

Kynurenic acid

Kynurenic acid is an endogenous neuroprotectant that is usually present in the brain at nanomolar concentrations. An antagonist to quinolinic acid, kynurenic acid acts on the glycine modulatory site of the NMDA receptor at low concentrations; and at higher concentrations, at the glutamate site of the NMDA receptors and also on the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. In addition, it also antagonizes the alpha 7 nicotinic acetylcholine receptors and selectively activates a G-protein coupled receptor, GPR35.

Increases in brain kynurenic acid were first observed to have sedative and anticonvulsant effects. Later, it was found to be protective against brain ischemia. The elevation in CSF kynurenic acid in schizophrenic patients also provided a new insight into the possible effect of kynurenic acid on the glutamatergic and dopaminergic systems, and its potential role in the pathogenesis of schizophrenia., Although it is argued that the physiological levels of kynurenic acid may fall below that which is necessary for glutamate receptor antagonism, at specific sites within synapses, those levels may be sufficient. This hypothesis is supported by the significant reduction in glutamate release and extracellular levels of dopamine seen with kynurenic acid in rats in vivo., In addition, the use of kynurenine 3-hydroxylase inhibitor also led to a hyperactivity in dopamine neurons.

In a septic shock mouse model, kynurenic acid was able to significantly decrease the release of tumour necrosis factor α (TNF-α), nitric oxide and high mobility group box 1 protein, a molecule likely to be involved in lipopolysaccharides mediated toxicity., Rather unexpectedly though, kynurenic acid inhibited the release of fibroblastic growth factor 1, a compound that supports growth and recovery of injured cells and enhances proliferation of glia cells. However, this does not necessarily challenge the concept of kynurenic acid being neuroprotective but definitely warrants more investigation.

3-hydroxyanthranilic acid

3-hydroxyanthranilic acid can be derived either from the hydrolysis of 3-hydroxykyurenine or the oxidation of anthranilic acid (Fig. 1). Besides playing a role in immunoregulation,– 3-hydroxyanthranilic acid is also a neurotoxin. Intracerebral injection of 3-hydroxyanthranilic acid leads to a decrease in choline acetyltransferase activity similar to those seen with quinolinic acid, but to a lesser extent. In addition, it is a free radical (superoxide and hydrogen peroxide) generator in the presence of copper. However, 3-hydroxyanthranilic acid can also act as an antioxidant, scavenging peroxyl radicals more effectively than equimolar concentrations of either ascorbic acid or Trolox (a water soluble analogue of vitamin E).

In murine macrophages, 3-hydroxyanthranilic acid at sub-millimolar concentrations can inhibit the activation of nuclear factor κB and likewise, the expression and activity of inducible nitric oxide synthase (iNOS). iNOS catalyses the formation of NO, which is strongly correlated with antimicrobial and antitumoral activities in mouse macrophages. Following along the lines of tumoregenesis, non-toxic concentrations of 3-hydroxyanthranilic acid has no effect on T cell receptor triggered CD8+ T lymphocyte proliferation, but greatly inhibits that induced by antigen-independent cytokine (particularly interleukin (IL)-2, IL-7 and IL-15) stimulation. Thus, in the context of cancer, tumour cells could severely arrest CD8+ T cell proliferation by driving cytokine production without effectively triggering T cell receptor response.

Furthermore, 3-hydroxyanthranilic acid exerts a selective apoptotic effect on murine thymocytes and T helper 1 (Thl) cells via the activation of caspase-8 and release of cytochrome c from mitochondria, but independent of the Fas pathway. This action occurs at concentrations well below those resulting in neurotoxicity or apoptosis of macrophages and could represent an important role in peripheral immunoregulation. Adding to this, following antigen stimulation of myelin basic protein Acl-11 T cell receptor transgenic CD4+ T cells, 3-hydroxyanthranilic acid was associated with a Gi/S phase arrest in CD4+ T cells and a cytokine profile shift in favour of Th2 cells. This finding has important implications in the treatment of multiple sclerosis (MS).

Picolinic acid

Picolinic acid, a monocarboxylic acid, is an endogenous neuroprotectant and a natural iron and zinc chelator. It controls cellular growth and has anti-tumoral, antifungal and antiviral activities. In vitro, picolinic acid arrests normal cells in G1 phase, possibly through the interactions with NAD+ as the inhibition can be overcome by nicotinamide. Recently, the characterization of the kynurenine pathway in human primary adult neurons and SK-N-SH neuroblastoma cell line found the former capable of synthesizing picolinic acid but not the latter. This variation in kynurenine pathway activation in neuroblastoma cells may provide a key to understanding tumour persistence and associated neurotoxicity.

In vivo, the antitumoral effect of picolinic acid was observed when treatment in mice inoculated with MBL-2 lymphoma cells altered their ribosomal ribonucleic acid (RNA) metabolism, augmenting the cytotoxic and tumoricidal activities of macrophages, resulting in increased survival rate., As an antifungal, picolinic acid acts synergistically with IFN-γ to amplify the inhibitory effect of neutrophils, inhibiting Candida albicans growth in vitro and in vivo., Although the mechanism of this co-stimulatory effect is unclear, it is known to be vulnerable to IL-4 suppression. In mouse, the synergy with IFN-γ is further extended to include NOS and TNF-α gene expression.,

At relatively high concentrations (1.5–3 mM), picolinic acid exerts antiviral, cytotoxic and apoptotic effects on HIV-1 and human herpes simplex virus-2, which is likely to be associated with an up-regulation in macrophage inflammatory protein (MIP)-1α and MIP-1β messenger RNA (mRNA) expression, as both compounds inhibit HIV-1 infection.– Interestingly, this stimulatory effect on MlP-lα and β is antagonized by IFN-γ. The complex interplay between picolinic acid and IFN-γ highlights the importance of these molecules on the regulation of macrophage activities and perhaps, the inflammatory response.

Like kynurenic acid, picolinic acid blocks quinolinic acid induced neurotoxicity, but not the neuroexcitatory component., Compared to kynurenic acid though, picolinic acid is less potent and appears to act via a different mechanism, attenuating calcium dependent glutamate release and/or chelating endogenous zinc.,, This lower potency of picolinic acid may also be partly explained by the weak stimulatory action it has on glutamate release from the striatum.

Quinolinic acid

Quinolinic acid is a heterocyclic amino acid that selectively activates the neuronal NMDA subtype of glutamate receptors. Within the brain, quinolinic acid concentrations are normally lower compared to blood and systemic tissues as tryptophan is metabolized to 5-hydroxytryptamine rather than to formylkynurenine. However, during an immune response, either systemic or central, IDO-1 activity and levels of quinolinic acid rise dramatically, the significance of which is still obscure.–

Under inflammatory conditions in the brain, infiltrating macrophages, microglia and dendritic cells are major sources of quinolinic acid production.,, Astrocytes, in contrast, are incapable of synthesizing quinolinic acid due to the absence of the enzyme, kynurenine hydroxylase. Rather, both astrocytes and neurons, being neuroprotective, uptake quinolinic acid and catabolize it to NAD. However, this catabolic system is easily saturated in the presence of high amounts of quinolinic acid, produced under pathological conditions, resulting in the toxic accumulation of quinolinic acid within the cells.

As an endogenous molecule of the mammalian CNS, the immune and neurotoxic properties of quinolinic acid are of special interest. In vitro, the synthesis of quinolinic acid by CD8−” dendritic cells induced apoptosis in Thl target cells; and quinolinic acid can also selectively inhibit the proliferation of CD4+ and CD8+ T lymphocytes and natural killer cells undergoing activation, the effect of which is amplified in the absence of tryptophan.

In direct intracerebral administration and neuronal cell cultures, quinolinic acid led to neuronal death., Similarly, the chronic exposure to sub-micromolar concentrations of quinolinic acid on neurons produced an adverse effect and the converse was true too., In vivo, injection of quinolinic acid into discrete regions of the rat brain caused axon-sparing lesions similar to those produced by kainic and ibotenic acid. Several studies have already provided strong evidence suggesting that quinolinic acid plays a significant pathological role in the development of neurodegenerative disorders, such as Huntington’s disease (HD), AD,, and AIDS dementia complex.,,

The Kynurenine Pathway in Disease States

Under various pathological conditions, an accelerated degradation of tryptophan with an accompanying increase in kynurenines is often observed in the serum, CSF and/or brain tissue (Tables 1, 2 and 3). Moreover, the breakdown of tryptophan via the kynurenine pathway is often routed preferentially towards the production of quinolinic acid. The pathologies associated with the up-regulation of the kynurenine pathway include infectious diseases (e.g. HIV), neurological disorders (e.g. AD, HD and ALS), affective disorders (e.g. schizophrenia, depression and anxiety), autoimmune diseases (e.g. MS and rheumatoid arthritis), peripheral conditions (e.g. cardiovascular disease) and malignancy (e.g. haematological neoplasia and colorectal cancer). However, significant elevations in tryptophan levels in lung and breast cancer have also been reported.

We also observed an increase in tryptophan levels ALS patients’ samples (unpublished). At this stage, we speculate that this phenomenon might be associated with either a disturbance in albumin binding of tryptophan, an over-compensatory response to decreased tryptophan concentrations in the brain and/or a malfunctioning in the L-type amino acid transporter at the blood brain barrier in ALS. The elevation in tryptophan notwithstanding, ALS patients still exhibited a larger kynurenine/tryptophan (K/T) ratio, an index for IDO activity, than control subjects due to a significant concomitant rise in kynurenine.

The enhanced degradation of tryptophan and higher K/T ratio are also often associated with advanced stages of disease, more severe symptoms or a fatal outcome., However, it is important to note that a progressive increased in tryptophan catabolism is part of the “normal” ageing process. Nonetheless, the degree of tryptophan depletion is still far more substantial in neurodegenerative disorders compared to normal ageing and most of the studies on pathological conditions were performed using age matched control subjects.,

In some studies, neopterin concentrations were also measured. Neopterin is a marker for immune activation and show a correlation with the K/T ratio and kynurenine, and inversely with tryptophan.,, This suggests an increase in endogenous IFN-γ production and an up-regulation in the kynurenine pathway. Indeed, HIV patients exhibit a 10-fold increase in IFN-γ through direct measurements.

When HIV patients are treated with highly active antiretroviral therapy (HAART) or antiretroviral treatment (ART), which significantly decreases immune activation through reduction in viral load, a repletion in tryptophan and reduction in kynurenine and quinolinic acid often follows., It is interesting to note that the alteration in tryptophan levels occurred in the absence of any dietary modification and that changes in K/T ratio correlated strongly with HIV mRNA and CD4+ T cell count.

The most important consequences of dramatic decline in tryptophan, thus, are likely to be immunosuppression and immunodeficiency, particularly evident in HIV infection, but also in autoimmune diseases and cancer. Other effects include weight loss, mood disturbances and cognitive impairment.,

In anorexia nervosa, underweight anorexic patients had lower tryptophan levels which rose with weight normalization. The association of tryptophan levels and the development of cachexia and weight loss are also evident in neoplasia., This could be associated with the release of pro-inflammatory cytokines. TNF-α, for instance, is a known cachexia, featuring prominently in muscle pathophysiology. The heightened catabolism of tryptophan via the kynurenine pathway may also divert this essential amino acid away from protein synthesis, thus, contributing to weight loss and muscle wasting.

Tryptophan also acts as a precursor for the synthesis of serotonin, which has a broad spectrum of action, two of which are in mood and cognitive functioning., Imbalances in kynurenines and significant decline in 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite, have been reported in major depression, MS and cardiovascular disease, among others.,, However, the activation of the immune response is also postulated as a cause of depression, and a strong association exists between inflammatory diseases and depression.,

In normal subjects, the deliberate depletion of tryptophan selectively impaired long-term memory consolidation, opposed to the results observed with the administration of selective serotonin reuptake inhibitors. In AD and HD patients, the K/T ratio was also inversely correlated with cognitive performance;, and in HIV-1 patients, treatment with HAART, which elevates tryptophan levels, markedly improved cognitive function.,

Potential Treatments Involving the Kynurenine Pathway

The involvement of the kynurenine pathway in a wide range of diseases suggests that research on treatment strategies targeting the kynurenine pathway (Fig. 2) may provide an alternative means of treatment or as a complement to what is already available.

Niacin supplementation

One of the consequences of accelerated degradation and depletion of tryptophan in the body is the suppression of T cell proliferation, which compromises the body’s immunity. Repletion of tryptophan could lead to improve immune response but may also inadvertently cause an increase in neurotoxins. Niacin supplementation, however, provides an indirect way to increase tryptophan and act as a feedback mechanism to suppress IDO-1 activity. In clinical studies, dietary supplementation of niacin to HIV-1 patients was associated with higher CD4 counts and improved survival rates.,

IDO inhibitors

The suppression of IDO-1 activity has been targeted directly in cancer research. Using transgenic mouse model of breast cancer, IDO-1 inhibitors, 1-methyl-DL-tryptophan and methyl-thiohydantoin-tryptophan, were able to potentiate the efficacy of chemotherapy drugs, promoting tumour regression without increasing the side effects. The discovery of the preferential inhibition by D-l-methyl-tryptophan on IDO-2 could also provide the key to understanding the mechanism behind the antitumoral action of 1-methyl-tryptophan and in designing future IDO inhibitors.

Kynurenine analogues

Another approach to modifying the kynurenine pathway is to skew the balance of kynurenines towards neuroprotection and away from neurotoxicity. Currently, there are several therapeutic agents, either already on the market or undergoing clinical trials, which are either analogues of neuroprotective kynurenines or act to inhibit the production of quinolinic acid. They include 4-chlorokynurenine, laquinimod, leflunomide, tranilast, nicotinylalanine, meta-nitrobenzoylalanine and Ro61-8048.

7-chlorokynurenate, a synthetic derivative of kynurenic acid, attenuates the neurotoxic effect of quinolinic acid through blockade of the glycine modulatory site of the NMDA receptor., However, 7-chlorokynurenate crosses the blood brain barrier with great difficulty. 4-chlorokynurenine, a precursor of 7-chlorokynurenate, on the other hand, is able to overcome this obstacle. When administered together with quinolinic acid in vivo, 4-chlorokynurenine was converted into the active 7-chlorokynurenate successfully, providing neuroprotection.,

Laquinimod (ABR-215062), a novel synthetic quinoline, has demonstrated immunomodulatory properties without immunosuppression in preclinical trials.– In MS animal model, experimental autoimmune encephalomyelitis (EAE), laquinimod delayed disease progression, inhibited infiltration of CD4+ T cells and macrophages into the CNS and modulated the immune response in favour of Th2/Th3 cytokines IL-4, IL-10 and transforming growth factor (TGF-P). Furthermore, in patients with relapsing MS, treatment with laquinimod successfully reduced the development of active lesions.

Leflunomide (Avara®), an immunosuppressive and anti-inflammatory prodrug is converted into terflunomide in vivo (A771126). Terflunomide is an inhibitor of mitochondrial dihydroorotate dehydrogenase, an essential enzyme for de novo pyrimidine synthesis. In 1998, the Food and Drug Administration (FDA, U.S.A.) approved leflunomide for the treatment of rheumatoid arthritis. Furthermore, in a recent phase II trial with MS patients, terflunomide proved well tolerated and effective in reducing active lesions.

Tranilast (Rizaben®), a synthetic anthranilic acid derivative drug, has the ability to inhibit the release of chemical mediators, TGF-É¿ and suppress angiogenesis., Tranilast has been effective against many diseases, such as allergic rhinitis, atopic dermatitis and bronchial asthma. Recently, when tested against EAE, tranilast inhibited the actions of Thl cells while enhancing those of Th2 cells, an action similar to that of natural tryptophan catabolites, 3-hydroxyanthranilic acid and 3-hydroxykynurenic acid.

Finally, kynurenine hydroxylase inhibitors are also effective in diverting the kynurenine pathway away from the synthesis of quinolinic acid towards that of kynurenic acid. These compounds include nicotinylalanine, meta-nitrobenzoylalanine and Ro61-8048. Nicotinylalanine, an analogue of kynurenine, protects the brain from induced seizures, and quinolinic acid induced striatal damage in the rat. With meta-nitrobenzoylalanine, sedation and anticonvulsant effects were achieved in rats, while reduced neuronal loss from brain ischemia were seen in gerbils. In immune activated mice, meta-nitronemzoylalanine also significantly decreased quinolinic acid production in the blood and brain. With Ro61-8048, there is an additional benefit of reducing glutamate levels in the extracellular spaces of the basal ganglia in rats, while maintaining the learning and memory process. In EAE rats, administration of Ro61-8048 significantly reduced the neurotoxic levels of 3-hydroxykynurenine and quinolinic acid in the CNS; and in a cerebral malaria mouse model, it significantly increased the neuroprotective levels of picolinic acid, prevented the development of neurological symptoms and prolonged survival by threefold. Like meta-nitrobenzoylalanine, Ro61-8048 too decreased neuronal loss due to brain ischemia.

Conclusion

The kynurenine pathway is an effective mechanism in modulating the immune response and in inducing immune tolerance. This is achieved by accelerating the degradation of tryptophan and the generation of kynurenines. The metabolites of the pathway, with their different inherent properties, can also synergize or antagonize the effects of one another. By measuring the levels of tryptophan, kynurenines and the K/T ratio under various pathological conditions, the degree of immune activation and the relationship between the kynurenine pathway and disease states may be gleaned. However, much research is still needed to fully understand the complex interaction between tryptophan, IDO and kynurenines among themselves and within the CNS and in the periphery. With the seemingly prevalent involvement of the kynurenine pathway in a wide range of different diseases and disorders, the knowledge gained from research focusing on the kynurenine pathway may be translated into designing novel and more effective treatment strategies.

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    Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med. 2002;196:459-68.

    Not in our library10.1084/jem.20020121

  33. 33.

    Terness P, Bauer TM, Rose L, et al. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med. 2002;196:447-57.

    Not in our library10.1084/jem.20020052

  34. 34.

    Moffett JR, Els T, Espey MG, Walter SA, Streit WJ, Namboodiri MA. Quinolinate immunoreactivity in experimental rat brain tumors is present in macrophages but not in astrocytes. Exp Neurol. 1997;144:287-301.

    Not in our library10.1006/exnr.1996.6365

  35. 35.

    Guillemin G, Brew BJ. Implications of the kynurenine pathway and quinolinic acid in Alzheimer’s disease. Redox Rep. 2002;7:199-206.

    Not in our library10.1179/135100002125000550

  36. 36.

    Guillemin G, Meininger V, Brew B. Implications for the kynurenine pathway and quinolinic acid in amyotrophic lateral sclerosis. Neurodegenerative diseases. 2006;2:166-76.

    Not in our library10.1159/000089622

  37. 37.

    Guillemin GJ, Kerr SJ, Brew BJ. Involvement of quinolinic acid in AIDS dementia complex. Neurotox Res. 2005c;7:103-23.

    Not in our library10.1007/bf03033781

  38. 38.

    Ting K, Brew BJ, Guillemin GJ, Takai K. Effect of quinolinic acid on gene expression in human astrocytes: Implications for Alzheimer’s disease. International Congress Series. 2007.

    Not in our library

  39. 39.

    Bruijn LI, Miller TM, Cleveland DW. Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci. 2004;27:723-49.

    Not in our library10.1146/annurev.neuro.27.070203.144244

  40. 40.

    Beal MF, Matson WR, Swartz KJ, Gamache PH, Bird ED. Kynurenine pathway measurements in Huntington’s disease striatum: evidence for reduced formation of kynurenic acid. J Neurochem. 1990;55:1327-39.

    Not in our library10.1111/j.1471-4159.1990.tb03143.x

  41. 41.

    LIM CK, Smythe GA, Stocker R, Brew BJ, Guillemin GJ, Takai K. Characterization of the kynurenine pathway in human oligodendrocytes. International Congress Series. 2007.

    Not in our library

  42. 42.

    Stoy N, Mackay GM, Forrest CM, et al. Tryptophan metabolism and oxidative stress in patients with Huntington’s disease. J Neurochem. 2005;93:611-23.

    Not in our library10.1111/j.1471-4159.2005.03070.x

  43. 43.

    Zamanakou M, Germenis AE, Karanikas V. Tumor immune escape mediated by indoleamine 2,3-dioxygenase. Immunol Lett. 2007;111:69-75.

    Not in our library10.1016/j.imlet.2007.06.001

  44. 44.

    Moroni F, Russi P, Lombardi G, Beni M, Carla V. Presence of kynurenic acid in the mammalian brain. J Neurochem. 1988;51:177-80.

    Not in our library10.1111/j.1471-4159.1988.tb04852.x

  45. 45.

    Stone TW. Neuropharmacology of quinolinic and kynurenic acids. Pharmacol Rev. 1993;45:309-79.

    Not in our library

  46. 46.

    Stone TW, Addae JI. The pharmacological manipulation of glutamate receptors and neuroprotection. Eur J Pharmacol. 2002;447:285-96.

    Not in our library10.1016/s0014-2999(02)01851-4

  47. 47.

    Hilmas C, Pereira EF, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque EX. The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neuro Sci. 2001;21:7463-73.

    Not in our library10.1523/jneurosci.21-19-07463.2001

  48. 48.

    Wang H, Liao H, Ochani M, et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med. 2004;10:1216-21.

    Not in our library10.1038/nm1124

  49. 49.

    Carpenedo R, Chiarugi A, Russi P, et al. Inhibitors of kynurenine hydroxylase and kynureninase increase cerebral formation of kynurenate and have sedative and anticonvulsant activities. Neuro Science. 1994;61:237-43.

    Not in our library10.1016/0306-4522(94)90227-5

  50. 50.

    Cozzi A, Carpenedo R, Moroni F. Kynurenine hydroxylase inhibitors reduce ischemic brain damage: studies with (m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]- benzene-sulfonamide (Ro 61–8048) in models of focal or global brain ischemia. J Cereb Blood Flow Metab. 1999;19:771-7.

    Not in our library10.1097/00004647-199907000-00007

  51. 51.

    Erhardt S, Blennow K, Nordin C, Skogh E, Lindstrom LH, Engberg G. Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci Lett. 2001;33:96-8.

    Not in our library10.1016/s0304-3940(01)02242-x

  52. 52.

    Grace AA. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience. 1991;41:1-24.

    Not in our library10.1016/0306-4522(91)90196-u

  53. 53.

    Scharfman HE, Goodman JH, Schwarcz R. Electrophysiological effects of exogenous and endogenous kynurenic acid in the rat brain: studies in vivo and in vitro. Amino Acids. 2000;19:283-97.

    Not in our library10.1007/s007260070060

  54. 54.

    Carpenedo R, Pittaluga A, Cozzi A, et al. Presynaptic kynurenate-sensitive receptors inhibit glutamate release. Eur J Neurosci. 2001;13:2141-7.

    Not in our library10.1046/j.0953-816x.2001.01592.x

  55. 55.

    Rassoulpour A, Wu HQ, Ferre S, Schwarcz R. Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatum. J Neurochem. 2005;93:762-5.

    Not in our library10.1111/j.1471-4159.2005.03134.x

  56. 56.

    Erhardt S, Oberg H, Mathe JM, Engberg G. Pharmacological elevation of endogenous kynurenic acid levels activates nigral dopamine neurons. Amino Acids. 2001b;20:353-62.

    Not in our library10.1007/s007260170032

  57. 57.

    Riedemann NC, Guo RF, Ward PA. Novel strategies for the treatment of sepsis. Nat Med. 2003;9:517-24.

    Not in our library10.1038/nm0503-517

  58. 58.

    Moroni F, Fossati S, Chiarugi A, Cozzi A. Kynurenic acid actions in brain and periphery. International Congress Series. 2007;1304:305-13.

    Not in our library

  59. 59.

    Serio CD, Cozzi A, Angeli I, et al. Kynurenic acid inhibits the release of the neurotrophic fibroblast growth factor (FGF)-l and enhances proliferation of glial cells, in vitro. Cell Mol Neurobiol. 2005.

    Not in our library10.1007/s10571-005-8469-y

  60. 60.

    Morita T, Saito K, Takemura M, et al. 3-Hydroxyanthranilic acid, an L-tryptophan metabolite, induces apoptosis in monocyte-derived cells stimulated by interferon-gamma. Ann Clin Biochem. 2001;38:242-51.

    Not in our library10.1258/0004563011900461

  61. 61.

    Fallarino F, Grohmann U, Vacca C, et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ. 2002;9:1069-77.

    Not in our library10.1038/sj.cdd.4401073

  62. 62.

    Lopez AS, Alegre E, Diaz-lagares A, Garcia-giron C, Coma MJ, Gonzalez A. Effect of 3-hydroxyanthranilic acid in the immunosuppressive molecules indoleamine dioxygenase and HLA-G in macrophages. Immunol Lett. 2008;117:91-5.

    Not in our library10.1016/j.imlet.2008.01.001

  63. 63.

    Christen S, Peterhans E, Stocker R. Antioxidant activities of some tryptophan metabolites: possible implication for inflammatory diseases. Proc Natl Acad Sci U S A. 1990;87:2506-10.

    Not in our library10.1073/pnas.87.7.2506

  64. 64.

    Sekkai D, Guittet O, Lemaire G, Tenu JP, Lepoivre M. Inhibition of nitric oxide synthase expression and activity in macrophages by 3-hydroxyanthranilic acid, a tryptophan metabolite. Arch Biochem Biophys. 1997;340:117-23.

    Not in our library10.1006/abbi.1997.9913

  65. 65.

    Nathan CF, Hibbs JB. Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol. 1991;3:65-70.

    Not in our library10.1016/0952-7915(91)90079-g

  66. 66.

    Weber WP, Feder-mengus C, Chiarugi A, et al. Differential effects of the tryptophan metabolite 3-hydroxyanthranilic acid on the proliferation of human CD8+ T cells induced by TCR triggering or homeostatic cytokines. Eur J Immunol. 2006;36:296-304.

    Not in our library10.1002/eji.200535616

  67. 67.

    Platten M, Ho PP, Youssef S, et al. Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science. 2005;310:850-5.

    Not in our library10.1126/science.1117634

  68. 68.

    Fernandez-pol JA, Bono VH, Johnson GS. Control of growth by picolinic acid: differential response of normal and transformed cells. Proc Natl Acad Sci U S A. 1977;74:2889-93.

    Not in our library10.1073/pnas.74.7.2889

  69. 69.

    Guillemin GJ, Cullen KM, Lim CK, et al. Characterization of the kynurenine pathway in human neurons. J Neurosci. 2007c;27:12884-92.

    Not in our library10.1523/jneurosci.4101-07.2007

  70. 70.

    Varesio L, Clayton M, Blasi E, Ruffman R, Radzioch D. Picolinic acid, a catabolite of tryptophan, as the second signal in the activation of IFN-gamma-primed macrophages. J Immunol. 1990;145:4265-71.

    Not in our library

  71. 71.

    Ruffmann R, Schlick R, Chirigos MA, Budzynsky W, Varesio L. Antiproliferative activity of picolinic acid due to macrophage activation. Drugs Exp Clin Res. 1987;13:607-14.

    Not in our library

  72. 72.

    Abe S, Hu W, Ishibashi H, Hasumi K, Yamaguchi H. Augmented inhibition of Candida albicans growth by murine neutrophils in the presence of a tryptophan metabolite, picolinic acid. J Infect Chemother. 2004;10:181-4.

    Not in our library10.1007/s10156-004-0311-9

  73. 73.

    Blasi E, Mazzolla R, Pitzurra L, Barluzzi R, Bistoni F. Protective effect of picolinic acid on mice intracerebrally infected with lethal doses of Candida albicans. Antimicrob Agents Chemother. 1993;37:2422-6.

    Not in our library10.1128/aac.37.11.2422

  74. 74.

    Cox GW, Chattopadhyay U, Oppenheim JJ, Varesio L. IL-4 inhibits the costimulatory activity of IL-2 or picolinic acid but not of lipopolysaccharide on IFN-gamma-treated macrophages. J Immunol. 1991;147:3809-14.

    Not in our library

  75. 75.

    Melillo G, Cox GW, Biragyn A, Sheffler LA, Varesio L. Regulation of nitric-oxide synthase mRNA expression by interferon-gamma and picolinic acid. J Biol Chem. 1994;269:8128-33.

    Not in our library

  76. 76.

    Pais TF, Appelberg R. Macrophage control of mycobacterial growth induced by picolinic acid is dependent on host cell apoptosis. J Immunol. 2000;164:389-97.

    Not in our library10.4049/jimmunol.164.1.389

  77. 77.

    Alkhatib G, Combadiere C, Broder CC, et al. CC CKR5: a Rantes MIP-1 alpha, MlP-lbeta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science. 1996;272:1955-8.

    Not in our library10.1126/science.272.5270.1955

  78. 78.

    Fernandez-pol JA, Klos DJ, Hamilton PD. Antiviral cytotoxic and apoptotic activities of picolinic acid on human immunodeficiency virus-1 and human herpes simplex virus-2 infected cells. Anticancer Res. 2001;21:3773-6.

    Not in our library

  79. 79.

    Bosco MC, Rapisarda A, Massazza S, Melillo G, Young H, Varesio L. The tryptophan catabolite picolinic acid selectively induces the chemokines macrophage inflammatory protein-1 alpha and -1 beta in macrophages. J Immunol. 2000;164:3283-91.

    Not in our library10.4049/jimmunol.164.6.3283

  80. 80.

    Cocchi F, Devico AL, Garzino-demo A, Arya SK, Gallo RC, Lusso P. Identification of Rantes MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science. 1995;270:1811-5.

    Not in our library10.1126/science.270.5243.1811

  81. 81.

    Rapisarda A, Pastorino S, Massazza S, Varesio L, Bosco MC. Antagonistic effect of picolinic acid and interferon-gamma on macrophage inflammatory protein-1 alpha/beta production. Cell Immunol. 2002;220:70-80.

    Not in our library10.1016/s0008-8749(03)00008-x

  82. 82.

    Beninger RJ, Colton AM, Ingles JL, Jhamandas K, Boegman RJ. Picolinic acid blocks the neurotoxic but not the neuroexcitant properties of quinolinic acid in the rat brain: evidence from turning behaviour and tyrosine hydroxylase immunohistochemistry. Neuroscience. 1994;61:603-12.

    Not in our library10.1016/0306-4522(94)90438-3

  83. 83.

    Jhamandas KH, Boegman RJ, Beninger RJ, Flesher S. Role of zinc in blockade of excitotoxic action of quinolinic acid by picolinic acid. Amino Acids. 1998;14:257-61.

    Not in our library10.1007/bf01345272

  84. 84.

    Vrooman L, Jhamandas K, Boegman RJ, Beninger RJ. Picolinic acid modulates kainic acid-evoked glutamate release from the striatum in vitro. Brain Res. 1993;627:193-8.

    Not in our library10.1016/0006-8993(93)90320-m

  85. 85.

    Cockhill J, Jhamandas K, Boegman RJ, Beninger RJ. Action of picolinic acid and structurally related pyridine carboxylic acids on quinolinic acid-induced cortical cholinergic damage. Brain Res. 1992;599:57-63.

    Not in our library10.1016/0006-8993(92)90852-z

  86. 86.

    Heyes MP, Chen CY, Major EO, Saito K. Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types. Biochem J. 1997;326(Pt 2):351-6.

    Not in our library10.1042/bj3260351

  87. 87.

    Heyes MP, Saito K, Crowley JS, et al. Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. Brain. 1992;115(Pt 5):1249-73.

    Not in our library10.1093/brain/115.5.1249

  88. 88.

    Flanagan EM, Erickson JB, Viveros OH, Chang SY, Reinhard JF. Neurotoxin quinolinic acid is selectively elevated in spinal cords of rats with experimental allergic encephalomyelitis. J Neurochem. 1995;64:1192-6.

    Not in our library10.1046/j.1471-4159.1995.64031192.x

  89. 89.

    Espey MG, Tang Y, Morse HC, Moffett JR, Namboodiri MA. Localization of quinolinic acid in the murine AIDS model of retrovirus-induced immunodeficiency: implications for neurotoxicity and dendritic cell immunopathogenesis. Aids. 1996;10:151-8.

    Not in our library10.1097/00002030-199602000-00004

  90. 90.

    Brew BJ, Corbeil J, Pemberton L, et al. Quinolinic acid production is related to macrophage tropic isolates of HIV-1. J Neurovirol. 1995;1:369-74.

    Not in our library10.3109/13550289509111026

  91. 91.

    Heyes MP, Achim CL, Wiley CA, Major EO, Saito K, Markey SP. Human microglia convert 1-tryptophan into the neurotoxin quinolinic acid. Biochem J. 1996;320(Pt 2):595-7.

    Not in our library10.1042/bj3200595

  92. 92.

    Moffett JR, Espey MG, Gaudet SJ, Namboodiri MA. Antibodies to quinolinic acid reveal localization in select immune cells rather than neurons or astroglia. Brain Res. 1993;623:337-40.

    Not in our library10.1016/0006-8993(93)91450-7

  93. 93.

    Guillemin GJ, Smith DG, Kerr SJ, et al. Characterisation of kynurenine pathway metabolism in human astrocytes and implications in neuropathogenesis. Redox Report. 2000;5:108-11.

    Not in our library10.1179/135100000101535375

  94. 94.

    Guillemin GJ, Brew BJ, Noonan CE, Takikawa O, Cullen KM. Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer’s disease hippocampus. Neuropathol Appl Neurobiol. 2005a;31:395-404.

    Not in our library10.1111/j.1365-2990.2005.00655.x

  95. 95.

    Wolfensberger M, Amsler U, Cuenod M, Foster AC, Whetsell WO, Schwarcz R. Identification of quinolinic acid in rat and human brain tissue. Neurosci Lett. 1983;41:247-52.

    Not in our library10.1016/0304-3940(83)90458-5

  96. 96.

    Belladonna ML, Grohmann U, Guidetti P, et al. Kynurenine pathway enzymes in dendritic cells initiate tolerogenesis in the absence of functional IDO. J Immunol. 2006;111:130-7.

    Not in our library10.4049/jimmunol.177.1.130

  97. 97.

    Schwarcz R, Whetsell WO, Mangano RM. Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science. 1983;219:316-8.

    Not in our library10.1126/science.6849138

  98. 98.

    Kim JP, Choi DW. Quinolinate neurotoxicity in cortical cell culture. Neuroscience. 1987;23:423-32.

    Not in our library10.1016/0306-4522(87)90066-2

  99. 99.

    Whetsell WO, Schwarcz R. Prolonged exposure to submicromolar concentrations of quinolinic acid causes excitotoxic damage in organotypic cultures of rat corticostriatal system. Neurosci Lett. 1989;97:271-5.

    Not in our library10.1016/0304-3940(89)90609-5

  100. 100.

    Widner B, Leblhuber F, Fuchs D. Increased neopterin production and tryptophan degradation in advanced Parkinson’s disease. J Neural Transm. 2002;109:181-9.

    Not in our library10.1007/s007020200014

  101. 101.

    Guillemin GJ, Brew BJ, Noonan CE, Takikawa O, Cullen KM. Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer’s disease hippocampus. Neuropathol Appl Neurobiol. 2005b;31:395-404.

    Not in our library10.1111/j.1365-2990.2005.00655.x

  102. 102.

    Guillemin GJ, Brew BJ, Noonan CE, Knight TG, Smythe GA, Cullen KM, Takai K. Mass spectrometric detection of quinolinic acid in microdissected Alzheimer’s disease plaques. International Congress Series. 2007a.

    Not in our library

  103. 103.

    Heyes MP, Brew BJ, Martin A, Markey SP, Price RW, Bhalla RB, Salazar A. Cerebrospinal fluid quinolinic acid concentrations are increased in acquired immune deficiency syndrome. Adv Exp Med Biol. 1991a;294:687-90.

    Not in our library10.1007/978-1-4684-5952-4_94

  104. 104.

    Heyes MP, Brew BJ, Martin A, et al. Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological status. Ann Neurol. 1991b;29:202-9.

    Not in our library10.1002/ana.410290215

  105. 105.

    Guillemin GJ, Kerr SJ, Brew BJ. Involvement of quinolinic acid in ADDS dementia complex. Neurotox Res. 2004;7:103-24.

    Not in our library10.1007/bf03033781

  106. 106.

    Cascino A, Cangiano C, Ceci F, et al. Increased plasma free tryptophan levels in human cancer: a tumor related effect. Anticancer Research. 1991;11:1313-6.

    Not in our library

  107. 107.

    Schroecksnadel K, Winkler C, Duftner C, Wirleitner B, Schirmer M, Fuchs D. Tryptophan degradation increases with stage in patients with rheumatoid arthritis. Clin Rheumatol. 2006;25:334-7.

    Not in our library10.1007/s10067-005-0056-6

  108. 108.

    Giusti RM, Maloney EM, Hanchard B, et al. Differential patterns of serum biomarkers of immune activation in human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis, and adult T-cell leukemia/lymphoma. Cancer Epidemiol Biomarkers Prev. 1996;5:699-704.

    Not in our library

  109. 109.

    Medana IM, Day NP, Salahifar-sabet H, et al. Metabolites of the kynurenine pathway of tryptophan metabolism in the cerebrospinal fluid of Malawian children with malaria. J Infect Dis. 2003;188:844-9.

    Not in our library10.1086/377583

  110. 110.

    Frick B, Schroecksnadel K, Neurauter G, Leblhuber F, Fuchs D. Increasing production of homocysteine and neopterin and degradation of tryptophan with older age. Clin Biochem. 2004;37:684-7.

    Not in our library10.1016/j.clinbiochem.2004.02.007

  111. 111.

    Schwarcz R, Rassoulpour A, Wu HQ, Medoff D, Tamminga CA, Roberts RC. Increased cortical kynurenate content in schizophrenia. Biol Psychiatry. 2001;50:521-30.

    Not in our library10.1016/s0006-3223(01)01078-2

  112. 112.

    Murr C, Gerlach D, Widner B, Dierich MP, Fuchs D. Neopterin production and tryptophan degradation in humans infected by Streptococcus pyogenes. Med Microbiol Immunol. 2001;189:161-3.

    Not in our library10.1007/s430-001-8023-3

  113. 113.

    Schroecksnadel K, Winkler C, Fuith LC, Fuchs D. Tryptophan degradation in patients with gynecological cancer correlates with immune activation. Cancer Lett. 2005;223:323-9.

    Not in our library10.1016/j.canlet.2004.10.033

  114. 114.

    Fuchs D, Moller AA, Reibnegger G, Werner ER, Werner-felmayer G, Dierich MP, Wachter H. Increased endogenous interferon-gamma and neopterin correlate with increased degradation of tryptophan in human immunodeficiency virus type 1 infection. Immunol Lett. 1991;28:207-11.

    Not in our library10.1016/0165-2478(91)90005-u

  115. 115.

    Look MP, Altfeld M, Kreuzer KA, et al. Parallel decrease in neurotoxin quinolinic acid and soluble tumor necrosis factor receptor p75 in serum during highly active antiretroviral therapy of HIV type 1 disease. AIDS Res Hum Retroviruses. 2000;16:1215-21.

    Not in our library10.1089/08892220050116989

  116. 116.

    Zangerle R, Widner B, Quirchmair G, Neurauter G, Sarcletti M, Fuchs D. Effective antiretroviral therapy reduces degradation of tryptophan in patients with HIV-1 infection. Clin Immunol. 2002;104:242-7.

    Not in our library10.1006/clim.2002.5231

  117. 117.

    Demitrack MA, Heyes MP, Altemus M, Pigott TA, Gold PW. Cerebrospinal fluid levels of kynurenine pathway metabolites in patients with eating disorders: relation to clinical and biochemical variable. Biol Psychiatry. 1995;37:512-20.

    Not in our library10.1016/0006-3223(94)00173-z

  118. 118.

    Schmitt JA, Wingen M, Ramaekers JG, Evers EA, Riedel WJ. Serotonin and human cognitive performance. Curr Pharm Des. 2006;12:2473-86.

    Not in our library10.2174/138161206777698909

  119. 119.

    Iwagaki H, Hizuta A, Tanaka N, Orita K. Decreased serum tryptophan in patients with cancer cachexia correlates with increased serum neopterin. Immunol Invest. 1995;24:467-78.

    Not in our library10.3109/08820139509066843

  120. 120.

    Denz H, Orth B, Weiss G, Herrmann R, Huber P, Wachter H, Fuchs D. Weight loss in patients with hematological neoplasias is associated with immune system stimulation. Clin Investig. 1993;71:37-41.

    Not in our library10.1007/bf00210961

  121. 121.

    Beutler B, Greenwald D, Hulmes JD, et al. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature. 1985;316:552-4.

    Not in our library10.1038/316552a0

  122. 122.

    Riedel WJ, Klaassen T, Schmitt JA. Tryptophan mood, and cognitive function. Brain Behav Immun. 2002;16:581-9.

    Not in our library10.1016/s0889-1591(02)00013-2

  123. 123.

    Myint AM, Kim YM, Verkerk R, Scharpe S, Steinbusch H, Leonard B. Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Disord. 2007;98:143-51.

    Not in our library10.1016/j.jad.2006.07.013

  124. 124.

    Maes M, Scharpe S, Meltzer HY, et al. Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response. Psychiatry Res. 1994;54:143-60.

    Not in our library10.1016/0165-1781(94)90003-5

  125. 125.

    Baig S, Halawa I, Qureshi GA. High performance liquid chromatography as a tool in the definition of abnormalities in monoamine and tryptophan metabolites in cerebrospinal fluid from patients with neurological disorders. Biomed Chromatogr. 1991;5:108-12.

    Not in our library10.1002/bmc.1130050304

  126. 126.

    Smith RS. The macrophage theory of depression. Med Hypotheses. 1991;35:298-306.

    Not in our library10.1016/0306-9877(91)90272-z

  127. 127.

    Wichers MC, Koek GH, Robaeys G, Verkerk R, Scharpe S, Maes M. IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry. 2005;10:538-44.

    Not in our library10.1038/sj.mp.4001600

  128. 128.

    Minden SL, Orav J, Reich P. Depression in multiple sclerosis. Gen Hosp Psychiatry. 1987;9:426-34.

    Not in our library10.1016/0163-8343(87)90052-1

  129. 129.

    Katon W, Sullivan MD. Depression and chronic medical illness. J Clin Psychiatry. 1990;51(Suppl 3–11).

    Not in our library

  130. 130.

    Riedel WJ, Klaassen T, Deutz NE, Van someren A, Van praag HM. Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation. Psychopharmacology (Berl). 1999;141:362-9.

    Not in our library10.1007/s002130050845

  131. 131.

    Harmer CJ, Bhagwagar Z, Cowen PJ, Goodwin GM. Acute administration of citalopram facilitates memory consolidation in healthy volunteers. Psychopharmacology (Berl). 2002;163:106-10.

    Not in our library10.1007/s00213-002-1151-x

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    Abrams B, Duncan D, Hertz-Picciotto I. A prospective study of dietary intake and acquired immune deficiency syndrome in HIV-seropositive homosexual men. J Acquir Immune Defic Syndr. 1993;6:949-58.

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    Muller AJ, Duhadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Binl potentiates cancer chemotherapy. Nat Med. 2005;11:312-9.

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    Foster AC, Willis CL, Tridgett R. Protection Against N-methyl-D-aspartate Receptor-Mediated Neuronal Degeneration In Rat Brain by 7-chlorokynurenate and 3-amino-l-hydroxypyrrolid-2-one, Antagonists at The Allosteric Site for Glycine. Eur J Neurosci. 1990;2:270-7.

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    Hokari M, Wu HQ, Schwarcz R, Smith QR. Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid. Neuroreport. 1996;8:15-8.

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    Wu HQ, Salituro FG, Schwarcz R. Enzyme-catalyzed production of the neuroprotective NMD A receptor antagonist 7-chlorokynurenic acid in the rat brain in vivo. Eur J Pharmacol. 1997;319:13-20.

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    Wu HQ, Lee SC, Schwarcz R. Systemic administration of 4-chlorokynurenine prevents quinolinate neurotoxicity in the rat hippocampus. Eur J Pharmacol. 2000;390:261-74.

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    Brunmark C, Runstrom A, Ohlsson L, et al. The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2002;130:163-72.

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    Zou LP, Abbas N, Volkmann I, et al. Suppression of experimental autoimmune neuritis by ABR-215062 is associated with altered Thl/Th2 balance and inhibited migration of inflammatory cells into the peripheral nerve tissue. Neuropharmacology. 2002;42:731-9.

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    Yang JS, Xu LY, Xiao BG, Hedlund G, Link H. Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Thl/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis rats. J Neuroimmunol. 2004;156:3-9.

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    Polman C, Barkhof F, Sandberg-wollheim M, Linde A, Nordle O, Nederman T. Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology. 2005;64:987-91.

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    Williamson RA, Yea CM, Robson PA, et al. Dihydroorotate dehydrogenase is a high affinity binding protein for A77 1726 and mediator of a range of biological effects of the immunomodulatory compound. J Biol Chem. 1995;270:22467-72.

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    O’connor PW, Li D, Freedman MS, et al. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology. 2006;66:894-900.

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    Suzawa H, Kikuchi S, Arai N, Koda A. The mechanism involved in the inhibitory action of tranilast on collagen biosynthesis of keloid fibroblasts. Jpn J Pharmacol. 1992;60:91-6.

    Not in our library10.1254/jjp.60.91

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    Isaji M, Miyata H, Ajisawa Y, Takehana Y, Yoshimura N. Tranilast inhibits the proliferation, chemotaxis and tube formation of human microvascular endothelial cells in vitro and angiogenesis in vivo. Br J Pharmacol. 1997;122:1061-6.

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    Pellicciari R, Natalini B, Costantino G, et al. Modulation of the kynurenine pathway in search for new neuroprotective agents. Synthesis and preliminary evaluation of (m-nitrobenzoyl)alanine, a potent inhibitor of kynurenine-3-hydroxylase. J Med Chem. 1994;37:647-55.

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    Connick JH, Heywood GC, Sills GJ, Thompson GG, Brodie MJ, Stone TW. Nicotinylalanine increases cerebral kynurenic acid content and has anticonvulsant activity. Gen Pharmacol. 1992;23:235-9.

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    Russi P, Alesiani M, Lombardi G, Davolio P, Pellicciari R, Moroni F. Nicotinylalanine increases the formation of kynurenic acid in the brain and antagonizes convulsions. J Neurochem. 1992;59:2076-80.

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    Harris CA, Miranda AR, Tanguay JJ, Boegman RJ, Beninger RJ, Jhamandas K. Modulation of striatal quinolinate neurotoxicity by elevation of endogenous brain kynurenic acid. Br J Pharmacol. 1998;124:391-9.

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    Chiarugi A, Carpenedo R, Molina MT, Mattoli L, Pellicciari R, Moroni F. Comparison of the neurochemical and behavioral effects resulting from the inhibition of kynurenine hydroxylase and/or kynureninase. J Neurochem. 1995;65:1176-83.

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    Chiarugi A, Moroni F. Quinolinic acid formation in immune-activated mice: studies with (m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(-3-nitrophenyl)thiazol-2yl]-benzenesul fonamide (Ro 61–8048), two potent and selective inhibitors of kynurenine hydroxylase. Neuropharmacology. 1999;38:1225-33.

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    Moroni F, Cozzi A, Carpendo R, Cipriani G, Veneroni O, Izzo E. Kynurenine 3-mono-oxygenase inhibitors reduce glutamate concentration in the extracellular spaces of the basal ganglia but not in those of the cortex or hippocampus. Neuropharmacology. 2005;48:788-95.

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    Chiarugi A, Cozzi A, Ballerini C, Massacesi L, Moroni F. Kynurenine 3-mono-oxygenase activity and neurotoxic kynurenine metabolites increase in the spinal cord of rats with experimental allergic encephalomyelitis. Neuroscience. 2001;102:687-95.

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    Clark CJ, Mackay GM, Smythe GA, Bustamante S, Stone TW, Phillips RS. Prolonged survival of a murine model of cerebral malaria by kynurenine pathway inhibition. Infect Immun. 2005;73:5249-51.

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    Werner ER, Fuchs D, Hausen A, et al. Tryptophan degradation in patients infected by human immunodeficiency virus. Biol Chem Hoppe Seyler. 1988;369:337-40.

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    Larsson M, Hagberg L, Norkrans G, Forsman A. Indole amine deficiency in blood and cerebrospinal fluid from patients with human immunodeficiency virus infection. J Neurosci Res. 1989;23:441-6.

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    Heyes MP, Saito K, Devinsky O, Nadi NS. Kynurenine pathway metabolites in cerebrospinal fluid and serum in complex partial seizures. Epilepsia. 1994;35:251-7.

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    Orlikov AB, Prakhye IB, Ryzov IV. Kynurenine in blood plasma and DST in patients with endogenous anxiety and endogenous depression. Biol Psychiatry. 1994;36:97-102.

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    Fujigaki S, Saito K, Takemura M, et al. Species differences in L-tryptophan-kynurenine pathway metabolism: quantification of anthranilic acid and its related enzymes. Arch Biochem Biophys. 1998;358:329-35.

    Not in our library10.1006/abbi.1998.0861

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    Heyes MP, Saito K, Lackner A, Wiley CA, Achim CL, Markey SP. Sources of the neurotoxin quinolinic acid in the brain of HIV1-infected patients and retrovirus-infected macaques. Faseb J. 1998;12:881-96.

    Not in our library10.1096/fasebj.12.10.881

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    Huengsberg M, Winer JB, Gompels M, Round R, Ross J, Shahmanesh M. Serum kynurenine-to-tryptophan ratio increases with progressive disease in HIV-infected patients. Clin Chem. 1998;44:858-62.

    Not in our library

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    Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancer · 2002
    No notice
  173. 173.

    Ilzecka J, Kocki T, Stelmasiak Z, Turski WA. Endogenous protectant kynurenic acid in amyotrophic lateral sclerosis. Acta Neurol Scand. 2003;107:412-8.

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    Schrocksnadel K, Widner B, Bergant A, et al. Longitudinal study of tryptophan degradation during and after pregnancy. Life Sci. 2003;72:785-93.

    Not in our library10.1016/s0024-3205(02)02304-4

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    Wirleitner B, Rudzite V, Neurauter G, et al. Immune activation and degradation of tryptophan in coronary heart disease. Eur J Clin Invest. 2003;33:550-4.

    Not in our library10.1046/j.1365-2362.2003.01186.x

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    Schrocksnadel K, Winkler C, Fuith LC, Fuchs D. Tryptophan degradation in patients with gynecological cancer correlates with immune activation. Cancer Lett. 2005;223:323-9.

    Not in our library10.1016/j.canlet.2004.10.033

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    Forrest CM, Mackay GM, Oxford L, Stoy N, Stone TW, Darlington LG. Kynurenine pathway metabolism in patients with osteoporosis after 2 years of drug treatment. Clin Exp Pharmacol Physiol. 2006;33:1078-87.

    Not in our library10.1111/j.1440-1681.2006.04490.x

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    Mackay GM, Forrest CM, Stoy N, et al. Tryptophan metabolism and oxidative stress in patients with chronic brain injury. Eur J Neurol. 2006;13:30-42.

    Not in our library10.1111/j.1468-1331.2006.01220.x

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    Darlington LG, Mackay GM, Forrest CM, Stoy N, George C, Stone TW. Altered kynurenine metabolism correlates with infarct volume in stroke. Eur J Neurosci. 2007;26:2211-21.

    Not in our library10.1111/j.1460-9568.2007.05838.x

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    Hartai Z, Juhasz A, Rimanoczy A, et al. Decreased serum and red blood cell kynurenic acid levels in Alzheimer’s disease. Neurochem Int. 2007;50:308-13.

    Not in our library10.1016/j.neuint.2006.08.012

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    Schrocksnadel K, Winkler C, Duftner C, Wirleitner B, Schirmer M, Fuchs D. Tryptophan degradation increases with stage in patients with rheumatoid arthritis. Clin Rheumatol. 2006;25:334-7.

    Not in our library10.1007/s10067-005-0056-6

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    Chen Y, Stankovic R, Cullen KA, et al. The kynurenine pathway and inflammation in amyotrophic lateral sclerosis. [Abstract]. Amyotroph Lateral Scler. (Suppl. 1);81.

    Not in our library10.1007/s12640-009-9129-7

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    Young SN, Joseph MH, Gauthier S. Studies on kynurenine in human cerebrospinal fluid: lowered levels in epilepsy. J Neural Transm. 1983;58:193-204.

    Not in our library10.1007/bf01252805

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    Gisslen M, Larsson M, Norkrans G, Fuchs D, Wachter H, Hagberg L. Tryptophan concentrations increase in cerebrospinal fluid and blood after zidovudine treatment in patients with HIV type 1 infection. AIDS Res Hum Retroviruses. 1994;10:947-51.

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    Heyes MP, Saito K, Milstien S, Schiff SJ. Quinolinic acid in tumors, hemorrhage and bacterial infections of the central nervous system in children. J Neurol Sci. 1995;133:112-8.

    Not in our library10.1016/0022-510x(95)00164-w

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    Medana IM, Hien TT, Day NP, et al. The clinical significance of cerebrospinal fluid levels of kynurenine pathway metabolites and lactate in severe malaria. J Infect Dis. 2002;185:650-6.

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    Rejdak K, Bartosik-psujek H, Dobosz B, et al. Decreased level of kynurenic acid in cerebrospinal fluid of relapsing-onset multiple sclerosis patients. Neurosci Lett. 2002;331:63-5.

    Not in our library10.1016/s0304-3940(02)00710-3

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    Nilsson LK, Linderholm KR, Engberg G, et al. Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. Schizophr Res. 2005;80:315-22.

    Not in our library10.1016/j.schres.2005.07.013

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    Atlas A, Gisslen M, Nordin C, Lindstrom L, Schwieler L. Acute psychotic symptoms in HIV-1 infected patients are associated with increased levels of kynurenic acid in cerebrospinal fluid. Brain Behav Immun. 2007;21:86-91.

    Not in our library10.1016/j.bbi.2006.02.005

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    Beal MF, Matson WR, Storey E, et al. Kynurenic acid concentrations are reduced in Huntington’s disease cerebral cortex. J Neurol Sci. 1992;108:80-7.

    Not in our library10.1016/0022-510x(92)90191-m

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    Pearson SJ, Reynolds GP. Increased brain concentrations of a neurotoxin, 3-hydroxykynurenine, in Huntington’s disease. Neurosci Lett. 1992;144:199-201.

    Not in our library10.1016/0304-3940(92)90749-w

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    Sardar AM, Bell JE, Reynolds GP. Increased concentrations of the neurotoxin 3-hydroxykynurenine in the frontal cortex of HIV1-positive patients. J Neurochem. 1995;64:932-5.

    Not in our library10.1046/j.1471-4159.1995.64020932.x

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    Bara H, Hainfellner JA, Kepplinger B, Mazal PR, Shchmid H, Budka. Kynurenic acid metabolism in the brain of HIV-1 infected patients. J Neural Transm. 2000;107:1127-38.

    Not in our library10.1007/s007020070026

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