Role Of Kynurenines Research Articles

The role of kynurenine and kynurenine metabolites in psoriasis

Abstract Objectives Psoriasis is a widespread immunological disease characterised by inflammation and primarily associated with skin and joint symptoms. The kynurenine pathway significantly influences inflammation and immune system activity. The aim of this study is to determine serum concentrations of kynurenine metabolites in patients with psoriasis and investigate their correlation with disease severity. Methods This study included 30 participants with psoriasis and 30 individuals without the disease as healthy controls. Serum levels of tryptophan, kynurenine, 3-OH anthranilic acid, quinolinic acid, 3-OH kynurenine, and kynurenic acid were determined by liquid chromatography-mass spectrometry (LC-MS/MS). Results Serum levels of kynurenic acid (p<0.001), tryptophan (p<0.001) and the tryptophan/kynurenine ratio (TKR) (p<0.001) were statistically significantly lower in psoriasis patients than in healthy controls, while levels of quinolinic acid (p=0.007) and kynurenine (p=0.001) were significantly higher. The Psoriasis Area Severity Index (PASI) correlated positively with 3-hydroxykynurenine and kynurenic acid. Conclusions Kynurenine metabolites are associated with the pathophysiology of psoriasis and could serve as valuable candidate markers for monitoring inflammation.

Role of Kynurenine and Its Derivatives in the Neuroimmune System.

In recent years, there has been a growing realization of intricate interactions between the nervous and immune systems, characterized by shared humoral factors and receptors. This interplay forms the basis of the neuroimmune system, the understanding of which will provide insights into the pathogenesis of neurological diseases, in which the involvement of the immune system has been overlooked. Kynurenine and its derivatives derived from tryptophan have long been implicated in the pathogenesis of various neurological diseases. Recent studies have revealed their close association not only with neurological disorders but also with sepsis-related deaths. This review provides an overview of the biochemistry of kynurenine and its derivatives, followed by a discussion of their role via the modulation of the neuroimmune system in various diseases.

Selective inhibition of indoleamine and tryptophan 2,3-dioxygenases: Comparative study on kynurenine pathway in cell lines via LC-MS/MS-based targeted metabolomics

In the last decade, the kynurenine pathway, which is the primary metabolic route for tryptophan (TRP) catabolism, has sparked great interest in the pharmaceutical sciences due to its role in immune regulation and cancer immunoediting. In this context, the development of cell-based assays might represent a tool to: i) characterize the cell secretome according to cell types; ii) gain more insight into the role of kynurenines in different disease scenarios; iii) screen hIDO1 (human indoleamine 2,3-dioxygenase) inhibitors and evaluate their effect on downstream TRP-catabolizing enzymes. This paper reports a validated Liquid Chromatography with tandem mass spectrometry (LC-MS/MS) method to simultaneously quantify TRP, L-kynurenine (KYN), xanthurenic acid (XA), 3-hydroxykynurenine (3OHKYN), kynurenic acid (KA), 3-hydroxyanthranilic acid (3OHAA), anthranilic acid (AA), 5-hydroxytryptamine (serotonin, 5HT) and tryptamine (TRYP) in Dulbecco’s Modified Eagle and Eagle’s Minimum Essential Media (DMEM and EMEM, respectively). The quantitative method was validated according to FDA, ICH and EMA guidelines, later applied: i) to assess the impact of selective inhibition of hIDO1 or hTDO (human tryptophan 2,3-dioxygenase) on the kynurenine pathway in A375 (melanoma), MDA-MB-231 (breast cancer), and U87 (glioblastoma) cell lines using multivariate analysis (MVA); ii) to determine the IC50 values of both well-known (i.e., epacadostat, linrodostat) and the novel hIDO1 inhibitor (i.e., BL5) in the aforementioned cell lines. The proposed LC-MS/MS method is reliable and robust. Furthermore, it is highly versatile and suitable for applications in the preclinical drug research and in vitro assays.

Decreased kynurenine in cerebrospinal fluid and potential role in neuromyelitis optica spectrum disorder.

Tryptophan (Trp) metabolism has been implicated in neuroinflammatory and neurodegenerative disorders, but its relationship with neuromyelitis optica spectrum disorder (NMOSD) is unclear. In this pilot study, cerebrospinal fluid (CSF) was prospectively collected from 26 NMOSD patients in relapse and 16 controls with noninflammatory diseases and 6 neurometabolites in the tryptophan metabolic pathway, including 5-hydroxytryptamine (5-HT), kynurenine (KYN), melatonin (MLT), 5-hydroxyindoleacetic acid (5HIAA), 3-hydroxy-o-aminobenzoic acid (3-HAA), and kynurenic acid (KYA), were measured by ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The association of Trp metabolites with NMOSD and its clinical parameters was evaluated. The role of KYN, which is a Trp metabolite involved in the binding of NMOSD-IgG antibody to aquaporin 4 (AQP4), was also evaluated in vitro. CSF KYN was significantly decreased in patients with relapsing NMOSD compared to controls, and CSF KYN was associated with CSF white blood cells in NMOSD. In vitro experiments showed that NMOSD-IgG specifically recognized KYN, which reversed the NMOSD-IgG-induced downregulation of AQP4 expression. Our results show that abnormal Trp metabolism occurs in NMOSD and that KYN might be a potential target for the treatment of AQP4-IgG-positive NMOSD patients.

The Role of Kynurenine and Its Metabolites in Comorbid Chronic Pain and Depression.

Chronic pain and depression affect millions of people worldwide, and their comorbidity tends to exacerbate the severity of each individual condition. Intersecting brain regions and molecular pathways could probably explain the unique yet complex bidirectional relationship between these two disorders. Recent studies have found that inflammatory reactions, frequently identified in both chronic pain and depression, stimulate certain enzymes in the kynurenine pathway, while concurrently suppressing others. Kynurenine, a major tryptophan derivative, and its metabolites have been implicated in several inflammation-associated pain syndromes and depressive mood disorders. Due to inflammation, 95% of tryptophan is metabolized via the kynurenine pathway, which drives the reaction towards the production of metabolites that have distinct roles in the pathophysiology of these disorders. Diminished levels of the neuroprotective metabolite, kynurenic acid (KYNA), and elevated levels of the neurotoxic metabolite, quinolinic acid (QUIN), have been frequently identified in human patients formally diagnosed with these disorders, as well as animal models commonly used in medical research. This review not only explores the epidemiology of comorbid chronic pain and depression, but also highlights the involvement of kynurenine and its metabolites, specifically KYNA and QUIN, in these pervasive conditions.

The Role of Kynurenines in Cognitive Dysfunction in Bipolar Disorder

Introduction: Chronic low-grade inflammation is suggested to play a pathophysiological role in bipolar disorder (BD) and its related cognitive dysfunctions. Although kynurenine (KYN) pathway metabolites are key inflammatory mediators, studies investigating the association between KYN metabolism and cognition in BD are scarce. We aimed to explore the relationship between KYN metabolism and cognitive functioning across different mood states in BD. Methods: Sixty-seven patients with BD (35 depressed and 32 [hypo] manic) and 29 healthy controls were included. Cognitive functioning was assessed at 3 time intervals (baseline, 4, and 8 months) assessing processing speed, sustained attention, verbal memory, working memory, and response inhibition. Plasma samples for quantification of 3-hydroxykynurenine, quinolinic acid, and kynurenic acid (KYNA) were concurrently provided. Linear mixed models were used for statistical analysis. Results: The manic group showed deficits in all assessed cognitive domains with the exception of verbal memory at all test moments. The bipolar depression group showed deficits in the processing speed at all test moments. Throughout the whole follow-up period, KYNA was significantly lower in both patient groups than in controls. Only in the bipolar depression group, low KYNA was associated with worse global cognitive functioning (B = 0.114, p = 0.02) and slower processing speed in particular (B = 0.139, p = 0.03). Conclusion: Only in the bipolar depression group, lower KYNA was associated with worse cognitive functioning. Future large-scale longitudinal studies are warranted to confirm the role of KYN metabolites in cognitive impairment in patients with BD and the possible therapeutic implications of this relationship.

Kynurenine as a potential biomarker in detecting reduced muscle endurance: metabolomic profiling of patients with heart failure and exercise intolerance

Abstract Aims Reduced muscle endurance (RME) in patients with HFpEF and HFrEF is associated with structural and metabolic changes in skeletal muscle. We investigated the role of kynurenine (Kyn) as a potential marker in detecting RME. Additionally, we described the likely distorted metabolic pathways in serum in patients with RME and both preserved (HFpEF) and reduced (HFrEF) ejection fraction. Methods Fifty-five participants were prospectively recruited (17 HFpEF, 18 HFrEF outpatients and 20 healthy controls, HC). All participants underwent echocardiography, CPET, isokinetic muscle function tests. Quantification of metabolites in serum was performed using liquid chromatography tandem mass spectrometry. Results In a linear regression, Kyn was an independent predictor for RME after adjusting for alanine, glutamate, ornithine, spermine and short-chain-ACs (B: −8.2 per 1μM increase, 95% CI: −13.01, −3.30, p=0.001). Kyn showed 83% sensitivity and 70% specificity (area under the curve 0.83) in detecting RME. Patients with RME and HFpEF showed reduced levels of long-chain-, medium-chain-, medium-/long-chain-ACs ratios and alanine (p<0.05). In patients with RME and HFrEF we observed reduced concentrations of AAs (p<0.05). Compared to HC, patients with HFpEF and HFrEF had reduced amino acid (AA)-concentrations except for branched-chain and aromatic AAs, and higher concentrations of acylcarnitines (ACs) and Kyn (p<0.05). Conclusions Kyn shows high potential as biomarker for detecting RME. RME was associated with impaired fatty acid oxidation rates in HFpEF patients and with reduced concentrations of AAs in those with HFrEF. Funding Acknowledgement Type of funding sources: None.

Quality of Life, Tryptophan Metabolites, and Neurotoxicity Assessments of Patients with Relapsed or Refractory B Cell Malignancies Undergoing CAR 20/19 - T Cell Therapy

Introduction Chimeric antigen receptor (CAR) T cell immunotherapy represents a novel and increasingly used treatment modality for patients with relapsed and/or refractory B cell malignancies. Acute neurological toxicities of CAR-T cell therapy (e.g. immune effector cell-associated neurotoxicity syndrome) are well described, though delayed cognitive and emotional functioning and quality of life (QOL) are less well studied, with mechanisms of all incompletely understood. Given the known bidirectional relationship between neuroinflammation and depression, and the role of kynurenine (Kyn) metabolism in both, we studied QOL through patient-reported outcomes (PROs) and neurotoxicity and their relationship to Kyn metabolites. Methods Patients with relapsed refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia treated with CAR-20/19-T cells on our Phase I/Ib clinical trial (NCT03019055) (N=16) were included. Patients were excluded if they had a history of previous allogeneic hematopoietic stem cell transplantation. Study subjects provided serum and PROs through self-report surveys at the following time points: baseline/ apheresis, Day-14 (D14), D28, and D90 post-intervention. The following scales were used to assess QOL: Inventory of Depression and Anxiety Symptoms (IDAS), Brief Pain Inventory (BPI), Fatigue Severity Index (FSI), and Pittsburgh Sleep Quality Index (PSQI). Tryptophan and its metabolites (kynurenine (Kyn), 3-Hydroxy-anthranilic Acid (3-HAA), 3-Hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA)) and neurotoxicity grades were measured for all 16 subjects. Patients were evaluated for neurotoxicity with the CTCAE 5.0. The measurements were log-transformed to stabilize the variances and allow modeling of the expected multiplicative effects. A mixed effects longitudinal model was used for all eligible patients to evaluate the impact of time on all PRO variables over the 4 timepoints through 90 days post CAR-T infusion. Neurotoxicity was evaluated two ways: as a categorical variable with 5 levels (0 to -4) and as a continuous variable. Results Depression symptoms improved over time with the lowest value at Day 90, though the changes were not statistically significant (P = .072). Remaining QOL PRO variables did not show statistically significant changes, tending to improve or remain stable over time (Table 1 & Figure 1). Mean Kyn levels significantly changed over time (P = .028; Table 2). This effect is most pronounced in patients with Grade 3/4 neurotoxicity where Kyn levels rise at Day 14 and Day 28 followed by a decrease by Day 90 (Figure 2). Among patients who exhibited neurotoxicities, baseline levels of 3-HAA and 3-HK before CAR-T therapy were elevated; though nonsignificant, similar trends were not observed in the other metabolites (Figure 2). These observations however were significant when neurotoxicity was evaluated as a continuous variable (Table 2) with 3-HAA and 3-HK higher in patients with higher grade neurotoxicities (P = .015 and .070). Conclusions Our findings suggest that CAR-T therapy does not impair QOL and may in fact result in improved mood in the early months following cell infusion, adding to recent literature about long-term QOL in CAR-T survivors. Here, we also identify elevated baseline 3-HAA and 3-HK levels as well as increased Kyn levels following CAR-T therapy, with the first two associated with worse neurotoxicity. Most interestingly, we find higher levels of 3-HAA and 3-HK in patients who experience neurotoxicities. Correlational studies will be needed to confirm potential relationships between PROs and metabolites. Disclosures Hari: Incyte Corporation: Consultancy; Takeda: Consultancy; BMS: Consultancy; Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy. Shah:Cell Vault: Research Funding; Miltenyi Biotec: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Incyte: Consultancy; TG Therapeutics: Consultancy; Verastim: Consultancy; Kite Pharma: Consultancy, Honoraria; Lily: Consultancy, Honoraria.

P.230 The role of kynurenines in cognitive disfunctioning in bipolar disorder

P.230 The role of kynurenines in cognitive disfunctioning in bipolar disorder

The Detrimental Effects of Kynurenine, a Tryptophan Metabolite, on Human Bone Metabolism.

Studies in aged mice support a role for kynurenine, a tryptophan metabolite, in age-induced bone loss; however, the role of kynurenine in human bone metabolism is not well understood. To assess whether the kynurenine level in bone marrow (BM) aspirates, directly reflecting the bone microenvironment, is associated with osteoporosis-related phenotypes and bone biochemical markers. A case-control study conducted in a clinical unit. BM samples were collected from 72 patients at the time of hip surgery for either fragility hip fracture (HF) (n = 27) or for other causes (n = 45). In these samples, kynurenine was measured by liquid chromatography-tandem mass spectrometry, and the levels of tartrate-resistant acid phosphatase 5b (TRAP5b), bone-specific alkaline phosphatase (BSALP), receptor activator of nuclear factor-κB ligand (RANKL), and osteoprotegerin (OPG) were measured by immunoassay. Age was positively correlated with BM kynurenine level. After adjustment for confounders, subjects with fragility HF had a 39.7% higher BM kynurenine level than those without, and the OR per SD increment in BM kynurenine level for fragility HF was 3.80. The BM kynurenine level was inversely associated with bone mass at the total femur. Higher kynurenine concentrations were significantly associated with higher TRAP-5b and RANKL levels, but not with BSALP and OPG levels, in BM plasma. These results suggest that increased kynurenine levels during aging may contribute to the bone fragility seen in the elderly through increased bone resorption, with a resultant imbalance in bone remodeling.

Abstract 5716: Functional evidence for an immunosuppressive role of kynurenine in cancer patients

Abstract Background: While being neglected for decades, tumor immune escape is now considered as a new paradigm that promotes tumor growth and evasion. Besides the prototypical PD1 / PDL1 axis, several mechanisms has been identified as important actor in immune editing process. Indoleamine 2,3 dioxygenase (IDO1), a first rate-limiting enzyme of the Kynurenine pathway, has been described to favor tolerance and immune escape through the production of a series of metabolites including L-Kynurenine. However, functional evidences have not yet been clearly demonstrated. Methods: We reconstituted in vitro a human immune - tumor cell synapse where ability of primary immune cells to promote tumor cell death has been kinetically followed through fluorescent-based live cell imaging in the presence and absence of L-Kynurenine. Two different donors as source of Peripheral Blood Mononuclear Cells (PBMCs) and three different tumor cell lines - namely IB115 and IB136 as sarcoma models & H1299 as reference lung adenocarcinoma model - have been used in this study. Finally, in order to determine cancer subtypes that might be highly exposed to Kynurenine pathway dysregulation and associated immune dysfunction, a comprehensive analysis of Kynurenine and Tryptophan levels was done in a series of 691 patients with advanced solid tumors Results: L-Kynurenine demonstrated a clear propensity to limit the immune cell-mediated tumor apoptosis elicited by TCR ligation - an event that was consistent within the two different donors and the three different cell lines. Interestingly, this immune suppressive feature of L-Kynurenine was associated with a limited amount of gamma-Interferon (IFNγ) in the cell culture supernatant while no effect was observed on Tumor Necrosis Factor alpha (TNFα). It's worth to note that L-Kynurenine had no effect on tumor cells without immune cells thus suggesting that Kynurenine has direct action on immune cells through which it limits their anti-tumor function -The Kyn/Trp ratio in cancer patients was significantly higher than that reported in healthy subjects (median: 71.2, range: 5.8-2825.2). Median value was the highest in breast cancer (126) and the lowest in colorectal (54) and pancreatic cancer (51) patients. No correlation with IDO1 tumor expression neither with systemic markers of inflammation (C-reactive protein) was observed. In conclusion, these results represent the first large description of the Kynurenine/Tryptophan ratio levels in cancer patients and the first functional evidence of a direct inhibition by Kynurenine of lymphocytes's effector functions. Citation Format: Alban Bessede, Antoine Italiano, Assia Chaïbi, Christophe Rey, Imane Nafia, Sylvestre le Moulec, Sophie Cousin, Maud Toulmonde, Céline Auzanneau, Marina Pulido. Functional evidence for an immunosuppressive role of kynurenine in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5716.

Abstract 5705: The key role of kynurenine in anti-PD-1 failure

Abstract Background: Immune checkpoint inhibitors have revolutionized treatment and outcome of severe and often fatal disease, as metastatic lung cancer, demonstrating long-term tumor control and extended patient survival. Unfortunately, only 25-30% of patients have a long-term benefit from immunotherapy, while the remaining 70-75% demonstrate primary or acquired resistance. Recently, indoleamine 2,3-dioxygenase (IDO) has been proposed as a possible mechanism of resistance to anti-PD1 treatment. Indeed, IDO catalyzes the degradation of tryptophan (Trp) into kynurenine (Kyn), which seems to enhance the activity of Treg, leading to an immunosuppressive microenvironment. Methods: The serum concentrations of Trp and Kyn were measured by high-performance liquid chromatography tandem mass spectrometry in 26 patients affected by non-small cell lung cancer (NCLSC) before the start of the second-line therapy with nivolumab. The IDO activity was expressed with Kyn/Trp ratio. The associations between Kyn/Trip ratio and early progression, PS, age, sex, brain metastases and pleural effusion were analyzed using Spearman test and Mann Whitney test. Results: 14 out of 26 patients (54%) presented early progression (defined as progression of the disease within 6 months from the beginning of nivolumab treatment). The median value of Kyn/Trp ratio was 0.073 (0.024-0.18). We found a significant association between Kyn/Trp ratio and early progression (p= 0.009), while no statistical associations were found between Kyn/Trp ratio and PS, age, sex, brain metastases and pleural effusion. Indeed, patients with early progressive disease presented a median value of Kyn/Trp ratio significantly higher than other patients (0.094 vs 0.052; p= 0.01). Conclusion: The pretreatment evaluation of IDO activity, expressed as Kyn/Trp ratio, seems to be associated with response to immunotherapy. In particular, higher Kyn/Trp ratio could predict resistance to anti-PD-1 treatment. These preliminary results suggest the possibility of using anti-PD-1 plus IDO inhibitor in patients with high level of Kyn/Trp ratio. Citation Format: Andrea Botticelli, Bruna Cerbelli, Luana Lionetto, Ilaria Zizzari, Annalina Pisano, Michela Roberto, Elisa Onesti, Francesca Romana DI Pietro, Chiara Napoletano, Laura Pizzuti, Patrizia Vici, Giulia D'Amati, Federica Mazzuca, Maurizio Simmaco, Marianna Nuti, Paolo Marchetti. The key role of kynurenine in anti-PD-1 failure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5705.

OP 13 The tryptophan metabolite kynurenine induces vasorelaxation in systemic maternal arteries – A new target for therapeutic intervention?

Introduction The important immunoregulatory role of Kynurenine (Kyn) pathway tryptophan metabolism in the placenta is well established. Activity of this pathway is reduced in pre-eclampsia. Recently Kyn was shown to relax blood vessels and reduce blood pressure in animal models [1] . In a small study of non-pregnant humans (n = 5), Kyn relaxed omental arteries; this was attenuated by Linopirdine (Lin; 10 μM), an inhibitor of type 7 voltage-gated potassium (Kv7) channels [2] . Objectives To determine if Kyn contributes to regulation of vascular tone in systemic resistance arteries in pregnancy. Materials and methods Omental resistance arteries ( Results Treatment with 1, 3 or 6 mM Kyn dose-dependently attenuated arterial constriction to U46619 (N = 4–8, p = 0.003); greatest effect was observed at an intermediate U46619 dose of 10–7 M (change in constriction: control −0.19 ± 0.08 vs Kyn 6 mM −0.61 ± 0.13). Kyn induced relaxation of pre-constricted omental arteries (N = 7, p = 0.032; 0.70 ± 0.11 vs. 0.35 ± 0.08). Treatment with Lin 10 μM had no effect on Kyn-induced relaxation (N = 5, p = ns; 0.22 ± 0.12 vs. 0.17 ± 0.03). Conclusion This is the first study to demonstrate that Kyn has vasorelaxant effects on systemic resistance arteries in pregnancy. This supports our hypothesis that restoring Kyn pathway activity in pre-eclampsia could be a novel therapeutic target to attenuate maternal features of the disease. Kyn-induced relaxation was not inhibited by Lin 10 μM as previously reported outwith pregnancy, suggesting incomplete inhibition of Kv7 channels or an alternate compensatory mechanism.

S.28.02 Role of kynurenine and glutamate in inflammation-induced depression

S.28.02 Role of kynurenine and glutamate in inflammation-induced depression

ISTRY 2013 Special Issue

The 13th international conference of the International Society for Tryptophan Research (ISTRY) has been held in Sydney, 7th to 9th of November 2012. It was a really successful meeting with high quality speakers and presentations. ISTRY 2013 has attracted attendees from 14 different countries—Australia, Austria, Belgium, Canada, England, France, Germany, Italy, Japan, Sultanate of Oman, Scotland, Singapore, Sweden and USA. A satellite meeting organized by the Japanese Society for Tryptophan Research (JSTRY) has been held in Brisbane on the 5th of November. This JSTRY meeting was very successful with more than 40 Japanese scientists present. The scientific program selected was deliberately as broad as possible, to highlight the growing interest in tryptophan metabolism in different research fields. Methodology, nutrition, sleep, development, immunity, inflammation, psychiatric disorders and therapeutic strategies have been presented and discussed at this conference. Tryptophan research is progressively gaining recognition, even if probably still not fast enough, and is becoming of significant interest in many scientific disciplines. Several of the ISTRY and JSTRY presenters have submitted manuscripts related to their respective presentations to this special issue of the International Journal of Tryptophan Research. Dr. Murakami has demonstrated that the activity of the enzymes of the kynurenine pathway is different between species, tissue and cell types in physiological conditions, highlighting once more the importance of choosing animal models and cell types carefully to evaluate changes in the kynurenine pathway in human physiologic and pathologic conditions. Dr. Fukushima has compared the levels of tryptophan in the serum of male and female subjects. He found significantly higher levels in males, but no significant differences in the kynurenine levels or the ratio of kynurenine to tryptophan. Prof Takikawa has reviewed the latest evidence of the involvement of the kynurenine pathway in cancer, focusing on the role of kynurenine, the aryl hydrocarbon receptor and the mechanisms associated with tumor growth and immunosuppression. Dr. Fukuwatari reported that the liver plays an essential role in nicotinamide supply and demonstrated that 67 mg of tryptophan intake leads to the formation of 1 mg of nicotinamide. He also showed that the conversion ratio of tryptophan to nicotinamide is enhanced from mid to late pregnancy. Dr. Ito has studied the psychological factors influencing the concentration of melatonin in the saliva and sleep quality. He reported that during the night, levels of salivary melatonin are higher in subjects with a depressive tendency, high-level anxiety or a neurotic personality. Dr. Blankfield has discussed how the activation of the kynurenine pathway by physical illnesses can cause neuropathic and immunological disorders associated with secondary neuropsychiatric symptoms. Dr. Poulain has described the presence of low-grade and chronic inflammation in the white adipose tissue in human obesity. She also reported a dysregulation of the tryptophan metabolism in both obese humans and mice, with one critical difference. There is a significant increase in IDO-1 expression in the adipose tissue of obese human subjects but not in obese or lean mice. These data highlight again the discrepancies between animal models and human pathology. Dr. Williams has reviewed the potential therapeutic strategies using kynurenine pathway metabolites or analogs for the treatment of rheumatoid arthritis. Administration of some of these molecules has already been tested and was able to significantly reduce both clinical and histological progression of experimental arthritis. Finally, Dr. Essa has reviewed the current insights on autism research related to oxidative stress, mitochondrial dysfunction and altered tryptophan metabolism in autism spectrum disorders. It is noteworthy to mention that interest in the journal has been growing strongly, with more than 200,000 hits as of May 2013 (Fig. 1). This is likely due to its visibility in Pubmed. The number of individual citations of International Journal of Tryptophan Research has also been growing. Figure 1 IJTR journal analytics, http://www.la-press.com/journal.php?pa=journal_analytics&journal_id=97, accessed 28.4.13. The 2012 Musajo Medal has been attributed to Professor Abdullah Badawy (Cardiff Metropolitan University, UK) and the recipient for the 2015 meeting will be Professor Robert Schwartz (Maryland Psychiatric Research Center, USA). The next ISTRY meeting will take place in the United States of America in San Antonio in 2015 and will be hosted by Prof Don Dougherty. We hope that many more scientists working on tryptophan research will join ISTRY over the next three years and attend this 14th ISTRY meeting.

P.2.d.004 Effect of antidepressants and cyclo-oxygenase-2 inhibitor on cytokines and tryptophan metabolites after immune challenge in astrocytes

The haemostatic and biochemical abnormalities participate in the progression of cardiovascular disease (CVD) in peritoneally dialysed (PD) patients. Recently, the role of kynurenine (KYN) pathway of tryptophan (TRP) degradation in the development of CVD has been postulated.The present study was undertaken to investigate haemostatic parameters, biochemical profiles and kynurenines in PD patients both with and without CVD compared to age- and sex-matched healthy controls.The multiple biochemical abnormalities were present in PD patients, particularly in those with CVD. Tissue factor (TF), its inhibitor (TFPI), prothrombin fragment 1 + 2 (F1 + 2), urokinase-type plasminogen activator (uPA), its soluble receptor (suPAR), plasmin/antiplasmin (PAP) complexes, KYN, kynurenic (KYNA) and quinolinic (QA) acids levels were significantly higher, whereas TRP was significantly lower in the PD patients than in the controls. Tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) were higher in the patients with CVD than in the patients without CVD and controls. PD patients with CVD had higher F1 + 2, and they had lower suPAR and KYNA levels compared with PD patients without CVD. KYNA was positively associated with TFPI, whereas its was inversely associated with F1 + 2 both in the whole PD group and in CVD patients. Logistic regression analysis showed that low KYNA, high glucose, low HDL-cholesterol levels and the duration of dialysis treatment were independently associated with the presence of CVD in PD patients.The present study suggests a relationship between kynurenine pathway of tryptophan degradation, haemostatic and biochemical disturbances and CVD prevalence in peritoneally dialyzed patients.

The role of kynurenines in the pathomechanism of amyotrophic lateral sclerosis and multiple sclerosis: therapeutic implications

Tryptophan is one of the essential amino acids, 80% of which is catabolised in the extrahepatic tissues by indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme of the kynurenine pathway. Metabolites along the kynurenine pathway have been implicated to play a role in the pathomechanism of neuroinflammatory and neurodegenerative disorders. Changes in the concentration levels of kynurenines can shift the balance to pathological conditions. The ability to influence the metabolism towards the neuroprotective branch of the kynurenine pathway, i.e. towards kynurenic acid (KYNA) synthesis, may be one option in preventing neurodegenerative diseases. Three potential therapeutic strategies could be feasible to develop drugs to live up to expectations: (1) chemically related drugs with better bioavailability and higher affinity to the binding sites of excitatory receptors; (2) prodrugs of KYNA, which easily cross the blood-brain barrier combined with an inhibitor of organic acid transport for enhancement of the brain KYNA concentration; (3) inhibitors of enzymes of the kynurenine pathway. In this review, we focus on aspects of the pathomechanism and therapeutic possibilities of amyotrophic lateral sclerosis and multiple sclerosis that may be influenced by kynurenines.

Haemostatic system, biochemical profiles, kynurenines and the prevalence of cardiovascular disease in peritoneally dialyzed patients

Introduction The haemostatic and biochemical abnormalities participate in the progression of cardiovascular disease (CVD) in peritoneally dialysed (PD) patients. Recently, the role of kynurenine (KYN) pathway of tryptophan (TRP) degradation in the development of CVD has been postulated. Materials and methods The present study was undertaken to investigate haemostatic parameters, biochemical profiles and kynurenines in PD patients both with and without CVD compared to age- and sex-matched healthy controls. Results The multiple biochemical abnormalities were present in PD patients, particularly in those with CVD. Tissue factor (TF), its inhibitor (TFPI), prothrombin fragment 1 + 2 (F 1 + 2 ) , urokinase-type plasminogen activator (uPA), its soluble receptor (suPAR), plasmin/antiplasmin (PAP) complexes, KYN, kynurenic (KYNA) and quinolinic (QA) acids levels were significantly higher, whereas TRP was significantly lower in the PD patients than in the controls. Tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) were higher in the patients with CVD than in the patients without CVD and controls. PD patients with CVD had higher F 1 + 2, and they had lower suPAR and KYNA levels compared with PD patients without CVD. KYNA was positively associated with TFPI, whereas its was inversely associated with F 1 + 2 both in the whole PD group and in CVD patients. Logistic regression analysis showed that low KYNA, high glucose, low HDL-cholesterol levels and the duration of dialysis treatment were independently associated with the presence of CVD in PD patients. Conclusions The present study suggests a relationship between kynurenine pathway of tryptophan degradation, haemostatic and biochemical disturbances and CVD prevalence in peritoneally dialyzed patients.

Kynurenines and oxidative status are independently associated with thrombomodulin and von Willebrand factor levels in patients with end-stage renal disease

Introduction Increased oxidative stress (SOX) is one of the most potent inductors of endothelial dysfunction in end-stage renal disease (ESRD) patients. Kynurenines are the metabolites of tryptophan (TRP) degradation in mammals. However, the role of kynurenines in the function of the endothelium is still not recognized. Materials and methods We determined the plasma concentrations of TRP, kynurenine (KYN), 3-hydroxykynurenine (3-HKYN), quinolinic acid (QA); markers of SOX: Cu/Zn superoxide dismutase (Cu/Zn SOD), malondialdehyde (MDA); and endothelial dysfunction markers: thrombomodulin (TM) and von Willebrand factor (vWF) levels in 148 ESRD patients and healthy controls. Results TM, vWF, KYN, 3-HKYN and QA levels were significantly elevated in ESRD patients compared to controls. TRP concentrations in uremics were significantly lower than in healthy people. Both dialyzed groups showed a significant increase Cu/Zn SOD and MDA levels compared to controls. TM and vWF were positively associated with kynurenine pathway metabolites: KYN, 3-HKYN, QA (all p < 0.001), and with SOX markers: Cu/Zn SOD (both p < 0.0001) and MDA levels (p < 0.05, and p < 0.0001; respectively) in the whole ESRD group. The positive relationship were between Cu/Zn SOD and KYN (p < 0.010), 3-HKYN and QA levels (both p < 0.0001), whereas MDA was correlated with 3-HKYN and QA concentrations (both p < 0.05). Multiple stepwise regression analysis showed that KYN metabolites and oxidative status were the independent variables significantly associated with increased both TM and vWF levels in uremic patients. Conclusions Our study demonstrated that kynurenine metabolites and increased oxidative status are independently and significantly associated with endothelial dysfunction in ESRD patients.

The role of kynurenines in disorders of the central nervous system: Possibilities for neuroprotection

The metabolism of tryptophan mostly proceeds through the kynurenine pathway. The biochemical reaction includes both an agonist (quinolinic acid) at the N-methyl- d-aspartate receptor and an antagonist (kynurenic acid). Besides the N-methyl- d-aspartate antagonism, an important feature of kynurenic acid is the blockade of the alpha7-nicotinic acetylcholine receptor and its influence on the alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor. Kynurenic acid has proven to be neuroprotective in several experimental settings. On the other hand, quinolinic acid is a potent neurotoxin with an additional and marked free radical-producing property. In consequence of these various receptor activities, the possible roles of these substances in various neurological disorders have been proposed. Moreover, the possibility of influencing the kynurenine pathway to reduce quinolinic acid and increase the level of kynurenic acid in the brain offers a new target for drug action designed to change the balance, decreasing excitotoxins and enhancing neuroprotectants. This review surveys both the early and the current research in this field, focusing on the possible therapeutic effects of kynurenines.