Kynurenine Pathway Metabolites in Humans: Disease and Healthy States
Abstract
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%.1 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.2 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.3 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.4–7 TDO resides primarily in the liver and is induced by tryptophan or corticosteroids.4 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.8–11 It is up-regulated by certain cytokines and inflammatory molecules, such as lipopolysaccharides, amyloid peptides and human immunodeficiency virus (HIV) proteins,5,12,13 but its most potent stimulant is interferon gamma (IFN-γ).14,15 IFN-γ is able to induce both the gene expression and enzymatic activity of IDO-1.16,17 Recently, an IDO related enzyme, IDO-2, was identified.7,6 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.7,6
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,18 the excitotoxin and N-methyl-D-aspartic acid (NMDA) receptor agonist, quinolinic acid,19 the NMDA antagonist, kynurenic acid,20 and the neuroprotectant, picolinic acid.21
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.22,23 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.24–26 In particular, the general control non-derepressible-2 (GCN2) kinase was identified as a key mediator in IDO-1 induced tryptophan depletion immunosuppression.27 The activation of GCN2 triggers a stress-response program that can result in cell-cycle arrest, differentiation, adaptation or apoptosis.28–30 Furthermore, some of the kynurenines, such as quinolinic acid and 3-hydroxyanthranilic acid, can also effectively suppress T cell proliferation.31 This inhibition appears to selectively target immune cells undergoing activation 32 and these kynurenines may act in concert to produce an additive effect.33 Lastly, the production of the excitotoxin quinolinic acid is often significantly increased following inflammation and resulting immune activation.34
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,35–43 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.
The Kynurenines
Kynurenic acid
Kynurenic acid is an endogenous neuroprotectant that is usually present in the brain at nanomolar concentrations.44 An antagonist to quinolinic acid, kynurenic acid acts on the glycine modulatory site of the NMDA receptor at low concentrations;45 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.46 In addition, it also antagonizes the alpha 7 nicotinic acetylcholine receptors47 and selectively activates a G-protein coupled receptor, GPR35.48
Increases in brain kynurenic acid were first observed to have sedative and anticonvulsant effects.49 Later, it was found to be protective against brain ischemia.50 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.51,52 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.53 This hypothesis is supported by the significant reduction in glutamate release and extracellular levels of dopamine seen with kynurenic acid in rats in vivo.54,55 In addition, the use of kynurenine 3-hydroxylase inhibitor also led to a hyperactivity in dopamine neurons.56
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.57,58 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.59 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,60–62 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.21 In addition, it is a free radical (superoxide and hydrogen peroxide) generator in the presence of copper.18 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).63
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).64 iNOS catalyses the formation of NO, which is strongly correlated with antimicrobial and antitumoral activities in mouse macrophages.65 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.66 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.66
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.61 This action occurs at concentrations well below those resulting in neurotoxicity or apoptosis of macrophages and could represent an important role in peripheral immunoregulation.61 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.67 This finding has important implications in the treatment of multiple sclerosis (MS).67
Picolinic acid
Picolinic acid, a monocarboxylic acid, is an endogenous neuroprotectant and a natural iron and zinc chelator.21 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.68 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.69 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.70,71 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.72,73 Although the mechanism of this co-stimulatory effect is unclear, it is known to be vulnerable to IL-4 suppression.74 In mouse, the synergy with IFN-γ is further extended to include NOS and TNF-α gene expression.75,76
At relatively high concentrations (1.5–3 mM), picolinic acid exerts antiviral, cytotoxic and apoptotic effects on HIV-1 and human herpes simplex virus-2,77 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.78–80 Interestingly, this stimulatory effect on MlP-lα and β is antagonized by IFN-γ.81 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.81
Like kynurenic acid, picolinic acid blocks quinolinic acid induced neurotoxicity, but not the neuroexcitatory component.21,82 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.83,84,85 This lower potency of picolinic acid may also be partly explained by the weak stimulatory action it has on glutamate release from the striatum.84
Quinolinic acid
Quinolinic acid is a heterocyclic amino acid that selectively activates the neuronal NMDA subtype of glutamate receptors.19 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.86 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.87–89
Under inflammatory conditions in the brain, infiltrating macrophages, microglia and dendritic cells are major sources of quinolinic acid production.90,91,92 Astrocytes, in contrast, are incapable of synthesizing quinolinic acid due to the absence of the enzyme, kynurenine hydroxylase.93 Rather, both astrocytes and neurons,9 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.94
As an endogenous molecule of the mammalian CNS, the immune and neurotoxic properties of quinolinic acid are of special interest.95In vitro, the synthesis of quinolinic acid by CD8−” dendritic cells induced apoptosis in Thl target cells;96 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.32
In direct intracerebral administration and neuronal cell cultures, quinolinic acid led to neuronal death.97,98 Similarly, the chronic exposure to sub-micromolar concentrations of quinolinic acid on neurons produced an adverse effect and the converse was true too.99,98In 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.97 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),99 AD100,101,102 and AIDS dementia complex.103,104,105
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.106
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.107108,109 However, it is important to note that a progressive increased in tryptophan catabolism is part of the “normal” ageing process.110 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.111,100
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.112,113,87 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.114
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.115,116 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.116
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.117,118
In anorexia nervosa, underweight anorexic patients had lower tryptophan levels which rose with weight normalization.117 The association of tryptophan levels and the development of cachexia and weight loss are also evident in neoplasia.119,120 This could be associated with the release of pro-inflammatory cytokines. TNF-α, for instance, is a known cachexia, featuring prominently in muscle pathophysiology.121 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.119
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.118,122 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.123,124,125 However, the activation of the immune response is also postulated as a cause of depression126,127 and a strong association exists between inflammatory diseases and depression.128,129
In normal subjects, the deliberate depletion of tryptophan selectively impaired long-term memory consolidation,130 opposed to the results observed with the administration of selective serotonin reuptake inhibitors.131 In AD and HD patients, the K/T ratio was also inversely correlated with cognitive performance;132,133 and in HIV-1 patients, treatment with HAART, which elevates tryptophan levels, markedly improved cognitive function.134,135
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,136 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.137 In clinical studies, dietary supplementation of niacin to HIV-1 patients was associated with higher CD4 counts and improved survival rates.138,139
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.140 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.7
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.141,142 However, 7-chlorokynurenate crosses the blood brain barrier with great difficulty.143 4-chlorokynurenine, a precursor of 7-chlorokynurenate, on the other hand, is able to overcome this obstacle.144 When administered together with quinolinic acid in vivo, 4-chlorokynurenine was converted into the active 7-chlorokynurenate successfully, providing neuroprotection.145,146
Laquinimod (ABR-215062), a novel synthetic quinoline, has demonstrated immunomodulatory properties without immunosuppression in preclinical trials.147–149 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).150 Furthermore, in patients with relapsing MS, treatment with laquinimod successfully reduced the development of active lesions.151
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.152 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.153
Tranilast (Rizaben®), a synthetic anthranilic acid derivative drug, has the ability to inhibit the release of chemical mediators, TGF-É¿ and suppress angiogenesis.154,155 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.67
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 Ro61-8048.156 Nicotinylalanine, an analogue of kynurenine, protects the brain from induced seizures157,158 and quinolinic acid induced striatal damage in the rat.159 With meta-nitrobenzoylalanine, sedation and anticonvulsant effects were achieved in rats,160 while reduced neuronal loss from brain ischemia were seen in gerbils.50 In immune activated mice, meta-nitronemzoylalanine also significantly decreased quinolinic acid production in the blood and brain.161 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.162 In EAE rats, administration of Ro61-8048 significantly reduced the neurotoxic levels of 3-hydroxykynurenine and quinolinic acid in the CNS;163 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.164 Like meta-nitrobenzoylalanine, Ro61-8048 too decreased neuronal loss due to brain ischemia.50
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.
| References | Pathology | Compound | Patients | Controls | Comments |
|---|---|---|---|---|---|
| Werner et al. 1988165 | HIV | TRP (μM) | 44.8 ± 8.4++ | 91.0 ± 22.0 | Neopterin levels were significantly increased in patients (39.1 ± 17.0 nM vs. 4.5 ± 1.5 nM). |
| KYN (μM) | 3.53 ± 0.89*** | 2.31 ± 0.77 | |||
| T/K ratio | 13.4 ± 3.7++ | 42.5 ± 13.7 | |||
| Larsson et al. 1989166 | HIV | TRP (μM) | 28.4 | 39.7 | Platelets bound serotonin (5-HT) (ng/109) significantly reduced in patients compared to controls (430 vs. 676). |
| Cascino et al. 1991106 | Cancer | TRP (μM) | 10.9 ± 5.2* (L-pre) | 4.7 ± 0.7 | L-pre: Lung cancer, pre-operation; B: Breast cancer; pt: post-operation; A:P < 0.05 from pre-op. TRP data here is that of free tryptophan. Total plasma TRP was similar between patients and controls, pre-operation and post-operation. |
| 6.6 ± 3.2* (B-pre) | |||||
| 7.1 ± 2.6*A (L-pt) | 5.4 ± 0.9 | ||||
| 4.6 ± l.lA (B-pt) | |||||
| Fuchs et al. 1991114 | HIV | TRP (μM) | 57.0 ± 2.8** (+) | 91.0 ± 6.63 | IFN-γ (U/I): 259 ± 70** in seropositive patients compared to 23.5 ± 1.7 in seronegative patients. |
| KYN (μM) | 3.45 ± 0.14** (+) | 2.31 ± 0.23 | |||
| Denz et al. 1993120 | Hematological neoplasias | TRP (μM) | 56.4 ± 13.1 (HD) | ≤65 | HD: Hodgkin’s disease; NHL: non-Hodgkin’s lymphoma; M/M: multiple myeloma/monoclonal gammopathy of unknown significance. An inverse correlation was found between TRP and weight loss in patients. |
| 50.5 ± 16.9+ (NHL) | |||||
| 44.9 ± 12.9+ (MM) | |||||
| KYN (μM) | 2.3 ± 1.1 (HD) | ≤3.5 | |||
| Heyes et al. 1994167 | Epilepsy (intractable complex partial seizure) | TRP (μM) | 85.2 ± 3.7* (I.I.) | 76.7 ± 4.7 | I.I.: inter-ictal; P.I.: post-ictal Data are shown only when differences were significant. Patients’ data are approximates as results were presented only with a bar graph. |
| KYN (μM) | 68.5 ± 3.7+ (I.I.) | 3.27 ± 0.3 | |||
| 70.4 ± 3.7+ (P.I.) | |||||
| KYNA (nM) | 55.6 ± 5.56+ (I.I.) | 32.1 ± 3.6 | |||
| 60.2 ± 7.4l** (P.I.) | |||||
| 3-HK (nM) | No difference | 383 ± 24 | |||
| QUIN (nM) | 73.1 ± 3.7*** (I.I.) | 432 ± 60 | |||
| 70.4 ± 3.7*** (P.I.) | |||||
| Orlikov et al. 1994168 | Anxiety (A) and Depression (D) | KYN (μM) | 9.32 ± 0.2*** (A) | 4.32 ± 0.3 | After treatment, the KYN concentrations returned back to normal. A significant correlation exists between KYN concentrations and anxiety severity. |
| 2.98 ± 0.01* (D) | |||||
| Fujigaki et al. 1998169 | None | KYN (μM) | 1.6 ± 0.1 | Species (human, macaques, rabbit, guinea pig, rat, gerbil and mouse) differences present in KYN and AA. | |
| AA (nM) | 16.5 ± 0.7 | ||||
| Heyes et al. 1998170 | HIV | QUIN (nM) | 16847 ± 3358** | 451 ± 78 | |
| Huengsberg et al. 1998171 | HIV | TRP (μM) | 33.2 | 56.3 | Asym: asymptomatic patients. KT ratio (×1000): 119.9 in patients; 50.5 in asymptomatic AIDS subjects; 34.9 in controls. K/T ratio had a reciprocal relationship with CD4+ count. |
| KYN (μM) | 3.98 | 1.98 | |||
| Look et al. 2000115 | HIV | TRP (μM) | 44.6 (pre) | 52.6 | pre: pre-treatment with HAART. Post-treatment saw a significant increase in TRP and a decrease in QUIN. |
| KYN (μM) | 4.1*** (pre) | 2.7 | |||
| KYNA (μM) | 27 (pre) | 30.1 | |||
| QUIN (nM) | 848+ (pre) | 303.3 | |||
| K/T (×103) | 108.2*** (pre) | 51.4 | |||
| Murr et al. 2001112 | Streptococcus pyogenes | TRP (μM) | 25.3** (STSS) | STSS: streptococcal toxic shock syndrome; data are median values. Neopterin levels: STSS (152 nM) vs. tonsillitis (12 nM). Neopterin levels correlated with kynurenine, K/T and inversely with tryptophan significantly. | |
| KYN (μM) | 12.8** (STSS) | ||||
| K/T (×103) | 560** (STSS) | ||||
| Murray et al. 2001137 | HIV | TRP (μM) | 49.4 ± 6.5 (pre) | pre: pre-treatment; post: post-treatment. Treatment with 3 g of nicotinamide daily for 2 mths. | |
| (Zangerle et al. 2002)116 | HIV | TRP (μM) | 44.1 ± 13.3 (pre) | 65.8 ± 12.8 | pre: pre-treatment with ART. 6 mths after ART, median increase in TRP was 20.2%, median decrease in KYN was 19.3% and median decrease in KT ratio was 28.1%. During ART, change in KT ratio significantly correlated with change in HIV RNA, CD4+ T cells and neopterin. |
| KYN (μM) | 3.01 ± 0.91 (pre) | 2.02 ± 0.66 | |||
| K/T (×103) | 79.2 ± 60.3 (pre) | 30.7 ± 8.7 | |||
| (Huang et al. 2002)172 | Colorectal cancer | TRP (μM) | 53.5* (median) | 63.7 | |
| KYN (μM) | 2.1 (median) | 2.0 | |||
| K/T (×103) | 42.9* | 31.8 | |||
| (Ilzecka et al. 2003)173 | ALS | KYNA (nM) | 57.8 ± 35.0 | 59.6 ± 20.5 | m/s.c.s.: mild/severe clinical status a: significantly lower KYNA in s.c.s. compared to m.c.s. There was no difference in serum KYNA and type of ALS onset. |
| 81.6 ± 41.2a (m.c.s.) | |||||
| 39.9 ± 14.7* (s.c.s.) | |||||
| Schrocksnadel et al. 2003174 | Rheumatoid arthritis | TRP (μM) | 44.95** (median) | 62.62 | |
| KYN (μM) | 1.86 (median) | 2.06 | |||
| K/T (×103) | 42.39** | 31.72 | |||
| Wirleitner et al. 2003175 | Coronary heart disease | TRP (μM) | 53.5 ± 9.26** | 65.9 ± 12.7 | Subdividing patients into 3 groups: 1, 2/3-artery disease and those with restenosis showed no significant difference in TRP or KYN between groups. |
| KYN (μM) | l.88 ± 0.53 | l.85 ± 0.51 | |||
| K/T (×103) | 36.3 ± 13.0** | 28.l ± 5.15 | |||
| Schrocksnadel et al. 2005176 | Gynaecological cancer | TRP (μM) | 43.5* (median) | 53.5 | Subdivision of patients found only those with ovarian cancer had significantly lower TRP than control. TRP, KYN or K/T did not correlate with disease stage. |
| KYN (μM) | 1.91 (median) | 1.73 | |||
| Stoy et al. 200542 | HD | Data in graphs: | The comparisons here are for baseline values only. The paper also looked at values after TRP depletion and loading. Big variations in QUIN values were observed but overall, the concentrations were similar between patients and controls. Neopterin levels were significantly increased in patients (18.6 ± 1.7 nM vs. 12.7 ± 0.8 nM). | ||
| TRP (μM) | No difference | ||||
| KYN (μM) | Higher** | ||||
| KYNA (μM) | No difference | ||||
| 3-HK (μM) | Lower* | ||||
| 3-HAA (μM) | Lower* | ||||
| QUIN (μM) | No difference | ||||
| K/T (×103) | Higher** | ||||
| Forrest et al. 2006177 | Osteoporosis | TRP (μM) | 36.69 ± 1.8 (pre) | 42.08 ± 2.28 | Patients were treated for 2 yrs with either raloxifene or disodium etidronate with calcium. |
| KYN (μM) | 1.87 ± 0.12 (pre) | 1.96 ± 0.11 | |||
| KYNA (nM) | 32.68 ± 2.98 (pre) | 24.76 ± 2.46 | |||
| 3-HAA (nM) | 1.04 ± 0.13* (pre) | 7.89 ± 1.15 | |||
| AA (nM) | 139 ± 14.7* (pre) | 21.56 ± 2.25 | |||
| Mackay et al. 2006178 | Chronic brain injury | Data in graphs: | The comparisons here are for baseline values only. The paper also looked at values after TRP depletion and loading. Big variations in QUIN values were observed but overall, the concentrations were similar between patients and controls. Neopterin levels were significantly increased in patients (18.8 ± 2.4 nM vs. 12.7 ± 0.8 nM). | ||
| TRP (μM) | No difference | ||||
| KYN (μM) | Higher* | ||||
| KYNA (μM) | Lower** | ||||
| 3-HK (uM) | Lower** | ||||
| 3-HAA (μM) | Lower* | ||||
| QUIN (μM) | No difference | ||||
| K/T (×103) | Higher** | ||||
| Darlington et al. 2007179 | Stroke | Data in graphs: | The comparisons were made at different time points after stroke and the values here are only baseline values. Various correlations between kynurenines, neopterin, peroxidation products and volume of brain damage were analysed and TRP metabolism may contribute to brain damage following stroke. | ||
| TRP (μM) | Lower+ | ||||
| KYN (μM) | Higher* | ||||
| 3-HAA (nM) | Lower+ | ||||
| AA (nM) | Higher** | ||||
| K/T (×103) | Higher+ | ||||
| Hartai et al. 2007180 | AD | KYN (μM) | 2.5 ± 0.1 | 2.01 ± 0.2 | In red blood cells, comparing patients to controls, KYNA (nM): 43.9 ± 5.9*vs. 67.4 ± 8.6; KYN (mM): 8.1 ± 0.5 vs. 9.3 ± 0.6. Activities of KAT I and II were similar in both instances in patients and controls. |
| KYNA (nM) | 15.82.31 ± 1.1* | 23.13 ± 2.2 | |||
| Myint et al. 2007123 | Major depressioin | TRP (μM) | 65.8 ± 15.57 | 69.71 ± 13.65 | |
| KYN (\M) | 1.81 ± 0.56 | 1.87 ± 0.43 | |||
| KYNA (nM) | 24.29 ± 8.09** | 35.95 ± 13.4 | |||
| 3-HAA (nM) | 24.53 ± 11.91 | 24.12 ± 7.3 | |||
| K/T (×103) | 25 ± 12* | 17 ± 14 | |||
| Schrocksnadel et al. 2006181 | Rheumatoid arthritis | TRP (μM) | 58.0 ± 19.3* | There was an inverse relation between TRP and the disease stage (P < 0.01) | |
| KYN (nM) | 2.20 ± 0.82* | ||||
| Chen et al. unpublished182 | ALS | TRP (μM) | 143.28 ± 5.64++ | 75.0 ± 10.5 | |
| KYN (μM) | 4.02 ± 0–2++ | 2.52 ± 0.19 | |||
| QUIN (MM) | 0.37 ± 0.018* | 0.30 ± 0.026 | |||
| PIC (MM) | 1.42 ± 0.087* | 2.38 ± 0.37 | |||
| K/T (×103) | 37 ± 2.5 | 39 ± 4 |
*P < 0.05;
**P < 0.01;
***P < 0.005;
+P < 0.001;
++P < 0.0001.
| Ref. | Pathology | Compound | Patients | Controls | Comments |
|---|---|---|---|---|---|
| Young et al. 1983183 | Epilepsy | TRP (μM) | 1.58 ± 0.61 | 1.66 ± 0.64 | CSF data shown here were from the lumbar region. Cisternal CSF showed no differences between patients and controls and there were no CSF gradient differences either. |
| KYN (nM) | 28.4 ± 15.3* | 43.9 ± 24.5 | |||
| 5-HIAA (nM) | 96.7 ± 37.7 | 117.2 ± 62.7 | |||
| Larsson et al. 1989166 | HIV | TRP (nM) | 1518 | 2179 | No significant change in 5-HIAA. |
| Baig et al. 1991125 | MS and Cerebro-vascular disease (CVD) | TRP (nM) | 1.25 ± 0.14+ (MS) | 2.02 ± 0.34 | Metabolites of the noradrenergic and dopaminergic systems [3-methoxy-4-hydroxyphenylglyco (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] were also found to be significantly different in MS and CVD patients compared to controls. |
| 3.34 ± 0.54+ (CVD) | |||||
| 5-HT (pM) | 5 ± 1* (MS) | 7 ± 2 | |||
| 5-HIAA (pM) | 116 ± 15** (MS) | 173 ± 20 | |||
| 299 ± 50** (CVD) | |||||
| Gisslen et al. 1994184 | HIV | TRP (nM) | 1097 (pre) | 3–14 months treatment with zidovudin. Decrease in neopterin correlated with increase in TRP. 5-hydroxyindoleacetic acid (5-HIAA). | |
| Heyes et al. 1994167 | Epilepsy (intractable complex partial) | TRP (μM) | No difference | 1.32 ± 0.13 | I.I.: inter-ictal; P.I.: post-ictal Data are shown only when differences were significant. Patients’ data are approximates as results were presented only with a bar graph. QUIN:KYNA in patients vs. controls: 61.1 ± 11.1** (I.I.), 58.3 ± 5.55***(P.I.) vs. 86.1 ± 19.4 |
| KYN (nM) | 68.1 ± 2.78+ (I.I.) | 42.2 ± 3.8 | |||
| 65.3 ± 2.78+ (P.I.) | |||||
| KYNA (nM) | No difference | 2.32 ± 0.35 | |||
| QUIN (nM) | 72.2.1 ± 2.78+ (I.I.) | 21.9 ± 2.8 | |||
| 68.1 ± 2.78+ (P.I.) | |||||
| Demitrack et al. 1995117 | Eating disorders (anorexia nervosa) | TRP (nM) | 1.9 ± 0.5 | 2.1 ± 0.3 | In anorectics, weight normalized restored all compounds tested to within the control range. The relative amount of QUIN (QUIN: KYNA) was significantly higher during the underweight phase for anorectics. Kynurenines were within control range for normal weight bulimics. |
| KYN (nM) | 25.6 ± 9.9 | 34.4 ± 12.3 | |||
| KYNA (nM) | 1.5 ± 0.5* | 2.8 ± 1.2 | |||
| QUIN (nM) | 13.4 ± 5.4 | 13.8 ± 4.3 | |||
| 5-HIAA (nM) | 107.2 ± 31.4* | 146.3 ± 30.2 | |||
| Heyes et al. 1995185 | CNS pathology | QUIN (nM) | 31 ± 5 (Hy) | 20 ± 2 | Hy: hydrocephalus; H: haemorrhage; T: tumour; C: CSF infection. Subjects were all children. Both TNF-a and IL-6 were increased, with a significant correlation between IL-6 and QUIN. |
| 200 ± 113** (H) | |||||
| 282 ± 82** (T) | |||||
| 1084 ± 549** (C) | |||||
| KYN (nM) | 185 ± 40 (Hy) | 54 ± 7 | |||
| 254 ± 128** (H) | |||||
| 1698 ± 589** (T) | |||||
| 2610 ± l 067** (C) | |||||
| Fujigaki et al. 1998169 | None | KYN (nM) | 29.1 ± 3.2 | Species (human, macaques, rabbit, guinea pig, rat, gerbil and mouse) differences detected in levels of KYN and AA. | |
| AA (nM) | 16.3 ± 4.2 | ||||
| Heyes et al. 1998170 | HIV | QUIN (nM) | 3789 ± 888** | 22.1 ± 2.1 | |
| Erhardt et al. 2001a51 | Schizophrenia | KYN (nM) | 1.67 ± 0.027* | 0.97 ± 0.07 | A correlation between age and KYN was found in schizophrenics. |
| Medana et al. 2002186 | Malaria (severe) | KYNA (μM) | 0.06 | 0.07 | None of the kynurenines were associated with convulsions or coma. |
| QUIN (μM) | 0.80++ | 0.07 | |||
| PIC (μM) | 0.19+ | 0.08 | |||
| Rejdak et al. 2002187 | MS | KYNA (nM) | 0.41** (MS) | MS: were patients with relapsing MS during remission or not progressing for at least 2 months; ID: infectious inflammatory disease; OND: non-inflammatory neurological disorders. MS had significantly lower KYNA than either ID or OND. | |
| Ilzecka et al. 2003173 | ALS | KYNA (nM) | 2.41 ± 1.7 (grp) | 1.59 ± 0.9 | Bul: bulbar onset; s.c.s: severe clinical status No significant difference between KYNA levels and gender and no correlation between KYNA and age. |
| 3.61 ± 2.0** (bul) | |||||
| 3.26 ± 2.1*(s.c.s.) | |||||
| Medana et al. 2003109 | Cerebral Malaria (Malawian children) | QUIN (μM) | 0.09 | For QUIN, KYNA and PIC, 72% (2%), 77% (43%) and 74% (38%) of Malawian children had higher levels than median (reference range) UK control levels respectively. Elevated levels of QUIN and PIC were associated with a fatal outcome. Other diseases tested include convulsions, sepsis and acute hepatitis. | |
| KYNA (μM) | 0.21 | ||||
| PIC (μM) | 0.18 | ||||
| Nilsson et al. 2005188 | Schizophrenia | KYNA (nM) | 1.45 ± 0.10* (grp) | 1.06 ± 0.06 | Grp: All patients; 1st: Drug naive, first episode patients; T: patients undergoing treatment with anti-psychotic drugs; no D: patients who had been treated but are now drug free. In patients, a positive correlation was found between KYNA levels and age. |
| 1.53 ± 0.19* (1st) | |||||
| 1.53 ± 0.17*(T) | |||||
| Atlas et al. 2007189 | HIV | KYNA (nM) median levels | 4.54 (psy.) 3.02 (no psy.) | 1.23 | psy: psychotic symptoms In controls, KYNA levels were significantly higher in females (2.29 nM) than males (1.10 nM) (P < 0.05). However, this gender difference was absent in the patient population. |
| Chen et al. unpublished182 | ALS | TRP (μM) | 5.02 ± 0.19 | 2.58 ± 0.16 | |
| KYN (μM) | 0.23 ± 0.0016 | 0.027 ± 0.001 | |||
| QUIN (μM) | 0.053 ± 0.0054* | 0.038 ± 0.006 | |||
| PIC (μM) | 0.36 ± 0.034 | 0.51 ± 0.11 | |||
| K/T(×103) | 43.7 ± 2 | 11.1 ± 0.8 |
*P < 0.05;
**P < 0.01;
***P < 0.005;
+P < 0.001;
++P < 0.0001.
| Ref. | Pathology | Compound | Patients | Controls | Comments |
|---|---|---|---|---|---|
| Beal et al. 199040 | HD | KYNA (nM) | 1.29 ± 0.14* (HD) | 5.10 ± 1.04 | PD: Parkinson’s disease; IS: ischemic stroke. 2-fold increase in KYN/KYNA in HD (P < 0.01). KYNA was found to be considerably lower in HD compared to controls and patients with other neurological disorders. |
| Beal et al. 1992190 | HD | TRP (ng/g) | 4658 ± 442** (i.t.) | 8053 ± 1120 | p.g.:precentral gyrus; f.c: frontal cortex; i.t.: inferior temporal; m.t: middle temporal; s.t: superior temporal. Kynurenine metabolites, tryptophan, indoleamines and tyrosine and metabolites were anaylzed in 8 different regions of the brain. The data presented here are only for kynurenine metabolites that were significantly different in patients compared to controls. |
| KYN (ng/g) | 2334 ± 33*** (i.t.) | 5884 ± 129 | |||
| KYNA (ng/g) | 223 ± 33** (m.t.) | 422 ± 83 | |||
| 3-HK(ng/g) | 18.4 ± 5.3** (p.g.) | 81.3 ± 18.1 | |||
| 17.9 ± 2.4* (f.c) | 31.2 ± 5.6 | ||||
| 16.0 ± 2.7*** (i.t.) | 70.04 ± 17.2 | ||||
| 17.0 ± 3.7** (m.t.) | 39.0 ± 6.4 | ||||
| 29.4 ± 9.7** (s.t.) | 130.3 ± 60.4 | ||||
| 26.8 ± 8.3** (i.t.) | 67.7 ± 19.6 | ||||
| Pearson and Reynolds. 1992191 | HDand AD | 3-HK(ng/g) | 110 ± 47**(HDt.c.) | 65 ± 56 | t.c: temporal cortex; f.c: frontal cortex; p: putamen In HD, a general increase in 3-HK was observed, rather than a region-specific one. In t.c. of AD cases, where neuronal loss was greater than in HD, suggested that 3-HK increases in HD is not due entirely to neuronal atrophy. |
| 82 ± 41 (ADt.c.) | 65 ± 33 | ||||
| 93 ± 60**(HDf.c.) | 33 ± 26 | ||||
| 65 ± 47*** (HD p) | 19 ± 14 | ||||
| Sardar et al. 1995192 | HIV | 3-HK(ng/g) | 71.3 ± 12.7 (grp)** | 19.95 ± 3.18 | N-D: HIV without dementia; D: HIV with dementia. Tissues were taken from the frontal cortex. Higher levels of 3-HK in D was not significantly different from N-D. 3-HA formation was an indicator for 3-hydroxykinurease (3-HKase) activity, which was highest in N-D. Thus, increase in 3-HK reflected an overall increase in KP, instead of a decrease in 3-HKase activity. |
| 3-HA formation (ng/h/g) | 64.9 ± 11.4 (N-D)** | 15.8 = t2.14 | |||
| 85.5 ± 32.8 (D)** | |||||
| 66.4 ± 11.5 (grp)** | |||||
| 61.6 ± 16.5 (N-D)** | |||||
| 75.5 ± 12.5 (D)** | |||||
| Heyes et al. 1998170 | HIV | QUIN (pmol/g) | 20942 ± 2959** (bg) | 72 ± 26 | bg: basal ganglia; wm: cortical white matter; gm: cortical grey matter. |
| 25397 ± 11435** (wm) | 75 ± 12 | ||||
| 26292 ± 8615** (gm) | 81 ± 20 | ||||
| Bara et al. 2000193 | HIV | KYN (pmol/mg) | 22.66 ± 5.38 (f.c.) | 12.08 ± 1.24 | f.c: frontal cortex; cb: cerebellum KAT I activity rose significantly in both frontal cortex and cerebellum (341% and 262% of control, respectively), whereas KAT II activity increased only in the frontal cortex (141% of control). |
| KYNA (pmol/mg) | 24.67 ± 2.62 (cb) | 16.33 ± 2.00 | |||
| 7.31 ± 1.33(f.c.) | 3.49 ± 0.55 | ||||
| 4.54 ± 0.87 (cb) | 2.77 ± 0.63 | ||||
| Schwarcz et al. 2001111 | Schizophrenia | KYN (ng/g) | 35.2 ± 28.0* (b.a.9) | 22.4 ± 14.3 | b.a.: Brodmann area KYN, KYNA and 3-HK were tested in b.a 9,10 and 19. Only data that were significantly different from controls are presented here. Positive correlation found between KYN and KYNA but not KYN and 3-HK. |
| KYNA (ng/g) | 40.3 ± 23.4* (b.a.l9) | 30.9 ± 10.8 | |||
| 1.9 ± 1.3* (b.a.9) | 2.9 ± 2.2 |
*P < 0.05;
**P < 0.01;
***P < 0.005;
+P < 0.001;
++P < 0.0001.
Footnotes
Disclosure
The authors report no conflicts of interest.
Acknowledgments
This study was funded by the Motor Neuron Disease Research Institute Association (Australia).
References
- 1. Binding of indole analogues to human serum albumin. Effects of fatty acidsJ Biol Chem1965240423543[PubMed][Google Scholar]
- 2. Neutral amino acid transport at the human blood-brain barrierJ Biol Chem1988263193927[PubMed][Google Scholar]
- 3. Tryptophan metabolism in the central nervous system: medical implicationsExpert Rev Mol Med20068127[PubMed][Google Scholar]
- 4. The role of tryptophan 2,3-dioxygenase in the hormonal control of tryptophan metabolism in isolated rat liver cells. Effects of glucocorticoids and experimental diabetesBiochem J1985229499504[PubMed][Google Scholar]
- 5. Biochemical and medical aspects of the indoleamine 2,3-dioxygenase-initiated L-tryptophan metabolismBiochem Biophys Res Commun2005338129[PubMed][Google Scholar]
- 6. Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and miceGene200739620313[PubMed][Google Scholar]
- 7. Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophanCancer Res20076770827[PubMed][Google Scholar]
- 8. Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neuronsGlia2005d491523[PubMed][Google Scholar]
- 9. Characterization of the Kynurenine Pathway in Human NeuronsJ Neuro sci2007b271288492[Google Scholar]
- 10. Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protectionJ Neuro chem200178113[Google Scholar]
- 11. Expression of the kynurenine pathway enzymes in human microglia and macrophagesAdv Exp Med Biol2003a52710512[PubMed][Google Scholar]
- 12. Lipopolysaccharide induction of indoleamine 2,3-dioxygenase is mediated dominantly by an IFN-gamma-independent mechanismEur J Immunol20013123138[PubMed][Google Scholar]
- 13. A beta 1–42 induces production of quinolinic acid by human macrophages and microgliaNeuroreport2003b1423115[PubMed][Google Scholar]
- 14. Specific induction of pulmonary indoleamine 2,3-dioxygenase by bacterial lipopolysaccharideCiba Found Symp1978199203[PubMed][Google Scholar]
- 15. Characteristics of interferon induced tryptophan metabolism in human cells in vitroBiochim Biophys Acta198910121407[PubMed][Google Scholar]
- 16. Interferon enhances tryptophan metabolism by inducing pulmonary indoleamine 2,3-dioxygenase: its possible occurrence in cancer patientsProc Natl Acad Sci U S A19868366226[PubMed][Google Scholar]
- 17. Regulation of indoleamine 2,3-dioxygenase gene expression in human fibroblasts by interferon-gamma. Upstream control region discriminates between interferon-gamma and interferon-alphaJ Biol Chem1990265198717[PubMed][Google Scholar]
- 18. 3-Hydroxykynurenine and 3-hydroxyanthranilic acid generate hydrogen peroxide and promote alpha-cry stallin cross-linking by metal ion reductionBiochemistry200039726675[PubMed][Google Scholar]
- 19. Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNSEur J Pharmacol1981724112[PubMed][Google Scholar]
- 20. An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acidBrain Res19822471847[PubMed][Google Scholar]
- 21. Quinolinate-induced cortical cholinergic damage: modulation by tryptophan metabolitesBrain Res199052918591[PubMed][Google Scholar]
- 22. Implications of interferon-induced tryptophan catabolism in cancer, auto-immune diseases and AIDSAdv Exp Med Biol19919442535[PubMed][Google Scholar]
- 23. Interferon gamma blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophanProc Natl Acad Sci U S A19848190812[PubMed][Google Scholar]
- 24. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell divisionImmunology200210745260[PubMed][Google Scholar]
- 25. Inhibition of T cell proliferation by macrophage tryptophan catabolismJ Exp Med1999189136372[PubMed][Google Scholar]
- 26. Prevention of allogeneic fetal rejection by tryptophan catabolismScience199828111913[PubMed][Google Scholar]
- 27. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenaseImmunity20052263342[PubMed][Google Scholar]
- 28. Coupling endoplasmic reticulum stress to the cell death programCell Death Differ20041137280[PubMed][Google Scholar]
- 29. The eIF-2alpha kinases and the control of protein synthesisFaseb J199610137887[PubMed][Google Scholar]
- 30. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growthEmbo J200524347081[PubMed][Google Scholar]
- 31. T cell apoptosis by kynureninesAdv Exp Med Biol200352718390[PubMed][Google Scholar]
- 32. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenaseJ Exp Med200219645968[PubMed][Google Scholar]
- 33. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolitesJ Exp Med200219644757[PubMed][Google Scholar]
- 34. Quinolinate immunoreactivity in experimental rat brain tumors is present in macrophages but not in astrocytesExp Neurol1997144287301[PubMed][Google Scholar]
- 35. Implications of the kynurenine pathway and quinolinic acid in Alzheimer’s diseaseRedox Rep20027199206[PubMed][Google Scholar]
- 36. Implications for the kynurenine pathway and quinolinic acid in amyotrophic lateral sclerosisNeurodegenerative diseases2006216676[PubMed][Google Scholar]
- 37. Involvement of quinolinic acid in AIDS dementia complexNeurotox Res2005c710323[PubMed][Google Scholar]
- 38. Effect of quinolinic acid on gene expression in human astrocytes: Implications for Alzheimer’s diseaseInternational Congress Series2007[Google Scholar]
- 39. Unraveling the mechanisms involved in motor neuron degeneration in ALSAnnu Rev Neurosci20042772349[PubMed][Google Scholar]
- 40. Kynurenine pathway measurements in Huntington’s disease striatum: evidence for reduced formation of kynurenic acidJ Neurochem199055132739[PubMed][Google Scholar]
- 41. Characterization of the kynurenine pathway in human oligodendrocytesInternational Congress Series2007[Google Scholar]
- 42. Tryptophan metabolism and oxidative stress in patients with Huntington’s diseaseJ Neurochem20059361123[PubMed][Google Scholar]
- 43. Tumor immune escape mediated by indoleamine 2,3-dioxygenaseImmunol Lett20071116975[PubMed][Google Scholar]
- 44. Presence of kynurenic acid in the mammalian brainJ Neurochem19885117780[PubMed][Google Scholar]
- 45. Neuropharmacology of quinolinic and kynurenic acidsPharmacol Rev19934530979[PubMed][Google Scholar]
- 46. The pharmacological manipulation of glutamate receptors and neuroprotectionEur J Pharmacol200244728596[PubMed][Google Scholar]
- 47. The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implicationsJ Neuro Sci200121746373[Google Scholar]
- 48. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsisNat Med200410121621[PubMed][Google Scholar]
- 49. Inhibitors of kynurenine hydroxylase and kynureninase increase cerebral formation of kynurenate and have sedative and anticonvulsant activitiesNeuro Science19946123743[Google Scholar]
- 50. 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 ischemiaJ Cereb Blood Flow Metab1999197717[PubMed][Google Scholar]
- 51. Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophreniaNeurosci Lett200133968[PubMed][Google Scholar]
- 52. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophreniaNeuroscience199141124[PubMed][Google Scholar]
- 53. Electrophysiological effects of exogenous and endogenous kynurenic acid in the rat brain: studies in vivo and in vitroAmino Acids20001928397[PubMed][Google Scholar]
- 54. Presynaptic kynurenate-sensitive receptors inhibit glutamate releaseEur J Neurosci20011321417[PubMed][Google Scholar]
- 55. Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatumJ Neurochem2005937625[PubMed][Google Scholar]
- 56. Pharmacological elevation of endogenous kynurenic acid levels activates nigral dopamine neuronsAmino Acids2001b2035362[PubMed][Google Scholar]
- 57. Novel strategies for the treatment of sepsisNat Med2003951724[PubMed][Google Scholar]
- 58. Kynurenic acid actions in brain and peripheryInternational Congress Series2007130430513[Google Scholar]
- 59. Kynurenic acid inhibits the release of the neurotrophic fibroblast growth factor (FGF)-l and enhances proliferation of glial cells, in vitroCell Mol Neurobiol2005[Google Scholar]
- 60. 3-Hydroxyanthranilic acid, an L-tryptophan metabolite, induces apoptosis in monocyte-derived cells stimulated by interferon-gammaAnn Clin Biochem20013824251[PubMed][Google Scholar]
- 61. T cell apoptosis by tryptophan catabolismCell Death Differ20029106977[PubMed][Google Scholar]
- 62. Effect of 3-hydroxyanthranilic acid in the immunosuppressive molecules indoleamine dioxygenase and HLA-G in macrophagesImmunol Lett2008117915[PubMed][Google Scholar]
- 63. Antioxidant activities of some tryptophan metabolites: possible implication for inflammatory diseasesProc Natl Acad Sci U S A199087250610[PubMed][Google Scholar]
- 64. Inhibition of nitric oxide synthase expression and activity in macrophages by 3-hydroxyanthranilic acid, a tryptophan metaboliteArch Biochem Biophys199734011723[PubMed][Google Scholar]
- 65. Role of nitric oxide synthesis in macrophage antimicrobial activityCurr Opin Immunol199136570[PubMed][Google Scholar]
- 66. Differential effects of the tryptophan metabolite 3-hydroxyanthranilic acid on the proliferation of human CD8+ T cells induced by TCR triggering or homeostatic cytokinesEur J Immunol200636296304[PubMed][Google Scholar]
- 67. Treatment of autoimmune neuroinflammation with a synthetic tryptophan metaboliteScience20053108505[PubMed][Google Scholar]
- 68. Control of growth by picolinic acid: differential response of normal and transformed cellsProc Natl Acad Sci U S A197774288993[PubMed][Google Scholar]
- 69. Characterization of the kynurenine pathway in human neuronsJ Neurosci2007c271288492[PubMed][Google Scholar]
- 70. Picolinic acid, a catabolite of tryptophan, as the second signal in the activation of IFN-gamma-primed macrophagesJ Immunol1990145426571[PubMed][Google Scholar]
- 71. Antiproliferative activity of picolinic acid due to macrophage activationDrugs Exp Clin Res19871360714[PubMed][Google Scholar]
- 72. Augmented inhibition of Candida albicans growth by murine neutrophils in the presence of a tryptophan metabolite, picolinic acidJ Infect Chemother2004101814[PubMed][Google Scholar]
- 73. Protective effect of picolinic acid on mice intracerebrally infected with lethal doses of Candida albicansAntimicrob Agents Chemother19933724226[PubMed][Google Scholar]
- 74. IL-4 inhibits the costimulatory activity of IL-2 or picolinic acid but not of lipopolysaccharide on IFN-gamma-treated macrophagesJ Immunol1991147380914[PubMed][Google Scholar]
- 75. Regulation of nitric-oxide synthase mRNA expression by interferon-gamma and picolinic acidJ Biol Chem1994269812833[PubMed][Google Scholar]
- 76. Macrophage control of mycobacterial growth induced by picolinic acid is dependent on host cell apoptosisJ Immunol200016438997[PubMed][Google Scholar]
- 77. CC CKR5: a Rantes MIP-1 alpha, MlP-lbeta receptor as a fusion cofactor for macrophage-tropic HIV-1Science199627219558[PubMed][Google Scholar]
- 78. Antiviral cytotoxic and apoptotic activities of picolinic acid on human immunodeficiency virus-1 and human herpes simplex virus-2 infected cellsAnticancer Res20012137736[PubMed][Google Scholar]
- 79. The tryptophan catabolite picolinic acid selectively induces the chemokines macrophage inflammatory protein-1 alpha and -1 beta in macrophagesJ Immunol2000164328391[PubMed][Google Scholar]
- 80. Identification of Rantes MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cellsScience199527018115[PubMed][Google Scholar]
- 81. Antagonistic effect of picolinic acid and interferon-gamma on macrophage inflammatory protein-1 alpha/beta productionCell Immunol20022207080[PubMed][Google Scholar]
- 82. Picolinic acid blocks the neurotoxic but not the neuroexcitant properties of quinolinic acid in the rat brain: evidence from turning behaviour and tyrosine hydroxylase immunohistochemistryNeuroscience19946160312[PubMed][Google Scholar]
- 83. Role of zinc in blockade of excitotoxic action of quinolinic acid by picolinic acidAmino Acids19981425761[PubMed][Google Scholar]
- 84. Picolinic acid modulates kainic acid-evoked glutamate release from the striatum in vitroBrain Res19936271938[PubMed][Google Scholar]
- 85. Action of picolinic acid and structurally related pyridine carboxylic acids on quinolinic acid-induced cortical cholinergic damageBrain Res19925995763[PubMed][Google Scholar]
- 86. Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell typesBiochem J1997326Pt 23516[PubMed][Google Scholar]
- 87. Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological diseaseBrain1992115Pt 5124973[PubMed][Google Scholar]
- 88. Neurotoxin quinolinic acid is selectively elevated in spinal cords of rats with experimental allergic encephalomyelitisJ Neurochem19956411926[PubMed][Google Scholar]
- 89. Localization of quinolinic acid in the murine AIDS model of retrovirus-induced immunodeficiency: implications for neurotoxicity and dendritic cell immunopathogenesisAids1996101518[PubMed][Google Scholar]
- 90. Quinolinic acid production is related to macrophage tropic isolates of HIV-1J Neurovirol1995136974[PubMed][Google Scholar]
- 91. Human microglia convert 1-tryptophan into the neurotoxin quinolinic acidBiochem J1996320Pt 25957[PubMed][Google Scholar]
- 92. Antibodies to quinolinic acid reveal localization in select immune cells rather than neurons or astrogliaBrain Res199362333740[PubMed][Google Scholar]
- 93. Characterisation of kynurenine pathway metabolism in human astrocytes and implications in neuropathogenesisRedox Report2000510811[PubMed][Google Scholar]
- 94. Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer’s disease hippocampusNeuropathol Appl Neurobiol2005a31395404[PubMed][Google Scholar]
- 95. Identification of quinolinic acid in rat and human brain tissueNeurosci Lett19834124752[PubMed][Google Scholar]
- 96. Kynurenine pathway enzymes in dendritic cells initiate tolerogenesis in the absence of functional IDOJ Immunol20061111307[PubMed][Google Scholar]
- 97. Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brainScience19832193168[PubMed][Google Scholar]
- 98. Quinolinate neurotoxicity in cortical cell cultureNeuroscience19872342332[PubMed][Google Scholar]
- 99. Prolonged exposure to submicromolar concentrations of quinolinic acid causes excitotoxic damage in organotypic cultures of rat corticostriatal systemNeurosci Lett1989972715[PubMed][Google Scholar]
- 100. Increased neopterin production and tryptophan degradation in advanced Parkinson’s diseaseJ Neural Transm20021091819[PubMed][Google Scholar]
- 101. Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer’s disease hippocampusNeuropathol Appl Neurobiol2005b31395404[PubMed][Google Scholar]
- 102. Mass spectrometric detection of quinolinic acid in microdissected Alzheimer’s disease plaquesInternational Congress Series2007a[Google Scholar]
- 103. Cerebrospinal fluid quinolinic acid concentrations are increased in acquired immune deficiency syndromeAdv Exp Med Biol1991a29468790[PubMed][Google Scholar]
- 104. Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological statusAnn Neurol1991b292029[PubMed][Google Scholar]
- 105. Involvement of quinolinic acid in ADDS dementia complexNeurotox Res2004710324[PubMed][Google Scholar]
- 106. Increased plasma free tryptophan levels in human cancer: a tumor related effectAnticancer Research19911113136[PubMed][Google Scholar]
- 107. Tryptophan degradation increases with stage in patients with rheumatoid arthritisClin Rheumatol2006253347[PubMed][Google Scholar]
- 108. 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/lymphomaCancer Epidemiol Biomarkers Prev19965699704[PubMed][Google Scholar]
- 109. Metabolites of the kynurenine pathway of tryptophan metabolism in the cerebrospinal fluid of Malawian children with malariaJ Infect Dis20031888449[PubMed][Google Scholar]
- 110. Increasing production of homocysteine and neopterin and degradation of tryptophan with older ageClin Biochem2004376847[PubMed][Google Scholar]
- 111. Increased cortical kynurenate content in schizophreniaBiol Psychiatry20015052130[PubMed][Google Scholar]
- 112. Neopterin production and tryptophan degradation in humans infected by Streptococcus pyogenesMed Microbiol Immunol20011891613[PubMed][Google Scholar]
- 113. Tryptophan degradation in patients with gynecological cancer correlates with immune activationCancer Lett20052233239[PubMed][Google Scholar]
- 114. Increased endogenous interferon-gamma and neopterin correlate with increased degradation of tryptophan in human immunodeficiency virus type 1 infectionImmunol Lett19912820711[PubMed][Google Scholar]
- 115. Parallel decrease in neurotoxin quinolinic acid and soluble tumor necrosis factor receptor p75 in serum during highly active antiretroviral therapy of HIV type 1 diseaseAIDS Res Hum Retroviruses200016121521[PubMed][Google Scholar]
- 116. Effective antiretroviral therapy reduces degradation of tryptophan in patients with HIV-1 infectionClin Immunol20021042427[PubMed][Google Scholar]
- 117. Cerebrospinal fluid levels of kynurenine pathway metabolites in patients with eating disorders: relation to clinical and biochemical variableBiol Psychiatry19953751220[PubMed][Google Scholar]
- 118. Serotonin and human cognitive performanceCurr Pharm Des200612247386[PubMed][Google Scholar]
- 119. Decreased serum tryptophan in patients with cancer cachexia correlates with increased serum neopterinImmunol Invest19952446778[PubMed][Google Scholar]
- 120. Weight loss in patients with hematological neoplasias is associated with immune system stimulationClin Investig1993713741[Google Scholar]
- 121. Identity of tumour necrosis factor and the macrophage-secreted factor cachectinNature19853165524[PubMed][Google Scholar]
- 122. Tryptophan mood, and cognitive functionBrain Behav Immun2002165819[PubMed][Google Scholar]
- 123. Kynurenine pathway in major depression: evidence of impaired neuroprotectionJ Affect Disord20079814351[PubMed][Google Scholar]
- 124. Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune responsePsychiatry Res19945414360[PubMed][Google Scholar]
- 125. High performance liquid chromatography as a tool in the definition of abnormalities in monoamine and tryptophan metabolites in cerebrospinal fluid from patients with neurological disordersBiomed Chromatogr1991510812[PubMed][Google Scholar]
- 126. The macrophage theory of depressionMed Hypotheses199135298306[PubMed][Google Scholar]
- 127. IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicityMol Psychiatry20051053844[PubMed][Google Scholar]
- 128. Depression in multiple sclerosisGen Hosp Psychiatry1987942634[PubMed][Google Scholar]
- 129. Depression and chronic medical illnessJ Clin Psychiatry199051Suppl 3–11discussion 12–4.[Google Scholar]
- 130. Tryptophan depletion in normal volunteers produces selective impairment in memory consolidationPsychopharmacology (Berl)19991413629[PubMed][Google Scholar]
- 131. Acute administration of citalopram facilitates memory consolidation in healthy volunteersPsychopharmacology (Berl)200216310610[PubMed][Google Scholar]
- 132. Activated immune system in patients with Huntington’s diseaseClin Chem Lab Med19983674750[PubMed][Google Scholar]
- 133. Tryptophan degradation and immune activation in Alzheimer’s diseaseJ Neural Transm200010734353[PubMed][Google Scholar]
- 134. Suppression of inflammatory neurotoxins by highly active antiretroviral therapy in human immunodeficiency virus-associated dementiaJ Infect Dis199817810007[PubMed][Google Scholar]
- 135. Outcome of patients with HIV-1-related cognitive impairment on highly active antiretroviral therapyAids200115195200[PubMed][Google Scholar]
- 136. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvationImmunol Today19992046973[PubMed][Google Scholar]
- 137. Increased plasma tryptophan in HIV-infected patients treated with pharmacologic doses of nicotinamideNutrition2001176546[PubMed][Google Scholar]
- 138. A prospective study of dietary intake and acquired immune deficiency syndrome in HIV-seropositive homosexual menJ Acquir Immune Defic Syndr1993694958[PubMed][Google Scholar]
- 139. Effects of micronutrient intake on survival in human immunodeficiency virus type 1 infectionAm J Epidemiol1996143124456[PubMed][Google Scholar]
- 140. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Binl potentiates cancer chemotherapyNat Med2005113129[PubMed][Google Scholar]
- 141. 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 GlycineEur J Neurosci199022707[PubMed][Google Scholar]
- 142. 7-Chlorokynurenate Blocks NMDA Receptor-Mediated Neurotoxicity in Murine Cortical CultureEur J Neurosci199022915[PubMed][Google Scholar]
- 143. Indole-2-carboxylates, novel antagonists of the N-methyl-D-aspartate (NMDA)-associated glycine recognition sites: in vivo characterizationNeuropharmacology19933213947[PubMed][Google Scholar]
- 144. Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acidNeuroreport19968158[PubMed][Google Scholar]
- 145. Enzyme-catalyzed production of the neuroprotective NMD A receptor antagonist 7-chlorokynurenic acid in the rat brain in vivoEur J Pharmacol19973191320[PubMed][Google Scholar]
- 146. Systemic administration of 4-chlorokynurenine prevents quinolinate neurotoxicity in the rat hippocampusEur J Pharmacol200039026174[Google Scholar]
- 147. The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitisJ Neuroimmunol200213016372[PubMed][Google Scholar]
- 148. 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 tissueNeuropharmacology2002427319[PubMed][Google Scholar]
- 149. Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Thl/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis ratsJ Neuroimmunol200415639[PubMed][Google Scholar]
- 150. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosisNat Genet2001291605[PubMed][Google Scholar]
- 151. Treatment with laquinimod reduces development of active MRI lesions in relapsing MSNeurology20056498791[PubMed][Google Scholar]
- 152. Dihydroorotate dehydrogenase is a high affinity binding protein for A77 1726 and mediator of a range of biological effects of the immunomodulatory compoundJ Biol Chem19952702246772[PubMed][Google Scholar]
- 153. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapsesNeurology200666894900[PubMed][Google Scholar]
- 154. The mechanism involved in the inhibitory action of tranilast on collagen biosynthesis of keloid fibroblastsJpn J Pharmacol199260916[PubMed][Google Scholar]
- 155. Tranilast inhibits the proliferation, chemotaxis and tube formation of human microvascular endothelial cells in vitro and angiogenesis in vivoBr J Pharmacol199712210616[PubMed][Google Scholar]
- 156. 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-hydroxylaseJ Med Chem19943764755[PubMed][Google Scholar]
- 157. Nicotinylalanine increases cerebral kynurenic acid content and has anticonvulsant activityGen Pharmacol1992232359[PubMed][Google Scholar]
- 158. Nicotinylalanine increases the formation of kynurenic acid in the brain and antagonizes convulsionsJ Neurochem199259207680[PubMed][Google Scholar]
- 159. Modulation of striatal quinolinate neurotoxicity by elevation of endogenous brain kynurenic acidBr J Pharmacol19981243919[PubMed][Google Scholar]
- 160. Comparison of the neurochemical and behavioral effects resulting from the inhibition of kynurenine hydroxylase and/or kynureninaseJ Neurochem199565117683[PubMed][Google Scholar]
- 161. 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 hydroxylaseNeuropharmacology199938122533[PubMed][Google Scholar]
- 162. Kynurenine 3-mono-oxygenase inhibitors reduce glutamate concentration in the extracellular spaces of the basal ganglia but not in those of the cortex or hippocampusNeuropharmacology20054878895[PubMed][Google Scholar]
- 163. Kynurenine 3-mono-oxygenase activity and neurotoxic kynurenine metabolites increase in the spinal cord of rats with experimental allergic encephalomyelitisNeuroscience200110268795[PubMed][Google Scholar]
- 164. Prolonged survival of a murine model of cerebral malaria by kynurenine pathway inhibitionInfect Immun200573524951[PubMed][Google Scholar]
- 165. Tryptophan degradation in patients infected by human immunodeficiency virusBiol Chem Hoppe Seyler198836933740[PubMed][Google Scholar]
- 166. Indole amine deficiency in blood and cerebrospinal fluid from patients with human immunodeficiency virus infectionJ Neurosci Res1989234416[PubMed][Google Scholar]
- 167. Kynurenine pathway metabolites in cerebrospinal fluid and serum in complex partial seizuresEpilepsia1994352517[PubMed][Google Scholar]
- 168. Kynurenine in blood plasma and DST in patients with endogenous anxiety and endogenous depressionBiol Psychiatry19943697102[PubMed][Google Scholar]
- 169. Species differences in L-tryptophan-kynurenine pathway metabolism: quantification of anthranilic acid and its related enzymesArch Biochem Biophys199835832935[PubMed][Google Scholar]
- 170. Sources of the neurotoxin quinolinic acid in the brain of HIV1-infected patients and retrovirus-infected macaquesFaseb J19981288196[PubMed][Google Scholar]
- 171. Serum kynurenine-to-tryptophan ratio increases with progressive disease in HIV-infected patientsClin Chem19984485862[PubMed][Google Scholar]
- 172. Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancerBr J Cancer20028616916[PubMed][Google Scholar]
- 173. Endogenous protectant kynurenic acid in amyotrophic lateral sclerosisActa Neurol Scand20031074128[PubMed][Google Scholar]
- 174. Longitudinal study of tryptophan degradation during and after pregnancyLife Sci20037278593[PubMed][Google Scholar]
- 175. Immune activation and degradation of tryptophan in coronary heart diseaseEur J Clin Invest2003335504[PubMed][Google Scholar]
- 176. Tryptophan degradation in patients with gynecological cancer correlates with immune activationCancer Lett20052233239[PubMed][Google Scholar]
- 177. Kynurenine pathway metabolism in patients with osteoporosis after 2 years of drug treatmentClin Exp Pharmacol Physiol200633107887[PubMed][Google Scholar]
- 178. Tryptophan metabolism and oxidative stress in patients with chronic brain injuryEur J Neurol2006133042[PubMed][Google Scholar]
- 179. Altered kynurenine metabolism correlates with infarct volume in strokeEur J Neurosci200726221121[PubMed][Google Scholar]
- 180. Decreased serum and red blood cell kynurenic acid levels in Alzheimer’s diseaseNeurochem Int20075030813[PubMed][Google Scholar]
- 181. Tryptophan degradation increases with stage in patients with rheumatoid arthritisClin Rheumatol2006253347[PubMed][Google Scholar]
- 182. The kynurenine pathway and inflammation in amyotrophic lateral sclerosis. [Abstract]Amyotroph Lateral SclerSuppl. 181[Google Scholar]
- 183. Studies on kynurenine in human cerebrospinal fluid: lowered levels in epilepsyJ Neural Transm198358193204[PubMed][Google Scholar]
- 184. Tryptophan concentrations increase in cerebrospinal fluid and blood after zidovudine treatment in patients with HIV type 1 infectionAIDS Res Hum Retroviruses19941094751[PubMed][Google Scholar]
- 185. Quinolinic acid in tumors, hemorrhage and bacterial infections of the central nervous system in childrenJ Neurol Sci19951331128[PubMed][Google Scholar]
- 186. The clinical significance of cerebrospinal fluid levels of kynurenine pathway metabolites and lactate in severe malariaJ Infect Dis20021856506[PubMed][Google Scholar]
- 187. Decreased level of kynurenic acid in cerebrospinal fluid of relapsing-onset multiple sclerosis patientsNeurosci Lett2002331635[PubMed][Google Scholar]
- 188. Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophreniaSchizophr Res20058031522[PubMed][Google Scholar]
- 189. Acute psychotic symptoms in HIV-1 infected patients are associated with increased levels of kynurenic acid in cerebrospinal fluidBrain Behav Immun2007218691[PubMed][Google Scholar]
- 190. Kynurenic acid concentrations are reduced in Huntington’s disease cerebral cortexJ Neurol Sci1992108807[PubMed][Google Scholar]
- 191. Increased brain concentrations of a neurotoxin, 3-hydroxykynurenine, in Huntington’s diseaseNeurosci Lett1992144199201[PubMed][Google Scholar]
- 192. Increased concentrations of the neurotoxin 3-hydroxykynurenine in the frontal cortex of HIV1-positive patientsJ Neurochem1995649325[PubMed][Google Scholar]
- 193. Kynurenic acid metabolism in the brain of HIV-1 infected patientsJ Neural Transm2000107112738[PubMed][Google Scholar]