Anthranilic Acid Concentration Research Articles

Kynurenines in heart failure with preserved ejection fraction: an influence of type 2 diabetes.

Given their association with inflammatory processes and oxidative stress, tryptophan metabolites involved in the kynurenine pathway (KP) play a role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes (T2D). The study aimed to examine the relationship between the parameters of HFpEF, as determined by transthoracic echocardiography, and metabolites of the KP. We prospectively included 120 patients with HFpEF, 60 with and 60 without T2D, and 55 controls. High‑performance liquid chromatography was used to quantify the serum metabolites of KP. Echocardiography was used to assess left ventricular systolic and diastolic function. The patients with HFpEF and T2D showed an increase in tryptophan, kynurenine, and anthranilic acid concentrations (P = 0.001, P <0.001, and P <0.001, respectively) with a concomitant decrease in 3‑hydroxykynurenine (P <0.001) and quinolinic acid (P = 0.003), as compared with those with HFpEF without T2D. Left ventricular and left atrial remodeling was more pronounced in the group with T2D, but differences between these parameters did not reach statistical significance. Left ventricular global longitudinal strain was lower in the subgroup of patients with HFpEF and T2D than in the subgroup without T2D (P = 0.003). The study showed altered tryptophan metabolism in patients with HFpEF, highlighting a possible connection. The findings suggest potential implications for targeted therapeutic strategies focusing on tryptophan metabolism and cardiac function in patients with HFpEF and T2D.

Abstract 1004: Higher circulating tryptophan metabolites are associated with improved survival among patients with stage I-III colorectal cancer: results from the FOCUS consortium

Abstract Introduction: Dysregulation of the tryptophan metabolic pathway has been linked to colorectal cancer (CRC) development. While circulating levels of tryptophan metabolites have been associated with a decreased risk of CRC, epidemiological studies assessing tryptophan metabolites in relation to CRC outcomes are limited. In this study, we investigated associations between biomarkers of the tryptophan metabolism and clinical outcomes in prospectively followed, non-metastatic CRC patients. Materials and Methods: A total of 2,102 patients with stage I-III CRC participated in six cohorts in the international FOCUS (folate dependent 1-carbon metabolism in colorectal cancer recurrence and survival) consortium. Preoperative circulating concentrations of tryptophan and its metabolites (kynurenine, kynurenic acid (KA), xanthurenic acid (XA), 3-hydroxy-anthralinic acid (HAA), anthranilic acid (AA), and picolinic acid (PA)) were measured by liquid chromatography-tandem mass spectrometry. Using Cox proportional hazards regression, we examined associations of tryptophan metabolites with overall survival (OS) and disease-free survival (DFS). Models were adjusted for patient age, sex, circulating creatinine levels, tumor site, tumor stage, and study site. Results: After a median follow-up of 3.2 years for OS, higher tryptophan levels were associated with a 25-44% better overall and disease-free survival (hazard ratio, HROS, 0.56; 95% confidence interval (CI), 0.41-0.76, HRDFS, 0.75; 95% CI, 0.57-0.99). Furthermore, the tryptophan metabolites XA and PA were associated with a better OS and DFS (XA: HROS, 0.74; 95% CI, 0.64-0.85, HRDFS, 0.84; 95% CI, 0.75-0.94; PA: HROS, 0.76; 95% CI, 0.64-0.92, HRDFS, 0.86; 95% CI, 0.75-0.99). No statistically significant associations were found between kynurenine, KA, HAA, and AA concentrations and OS and DFS. The kynurenine-to-tryptophan ratio was positively associated with worse CRC survival (HROS, 2.12; 95% CI, 1.57-2.88, HRDFS, 1.32; 95% CI, 1.01-1.73). Conclusion: Higher preoperative circulating tryptophan and its metabolites XA and PA are associated with improved OS and DFS. Furthermore, the kynurenine-to-tryptophan ratio may represent a promising predictor for survival among stage I-III CRC patients. Citation Format: Victoria Damerell, Stefanie Brezina, Jennifer Ose, Anne JMR Geijsen, Arve Ulvik, Eline H. van Roekel, Andreana N. Holowatyj, Dieuwertje E. Kok, Fränzel JB van Duijnhoven, Christopher I. Li, Nina Habermann, Alexis B. Ulrich, Ellen Kampman, Matty P. Weijenberg, Andrea Gsur, Per M. Ueland, Martin Schneider, Cornelia M. Ulrich, Biljana Gigic, FOCUS Consortium. Higher circulating tryptophan metabolites are associated with improved survival among patients with stage I-III colorectal cancer: results from the FOCUS consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1004.

HTR1A, TPH2, and 5-HTTLPR Polymorphisms and Their Impact on the Severity of Depressive Symptoms and on the Concentration of Tryptophan Catabolites during Hepatitis C Treatment with Pegylated Interferon-α2a and Oral Ribavirin (PEG-IFN-α2a/RBV).

Seeing that there are no data about associations between serotonin gene polymorphism and tryptophan catabolite concentration during PEG-IFN-α2a treatment, the aim of the current study is to examine (a) the associations between polymorphisms within the HTR1A, TPH2, and 5-HTT genes and the severity of depression symptoms and (b) the relationships among rs6295, rs4570625, and 5-HTTLPR rs25531polymorphisms and indoleamine 2,3-dioxygenase (IDO) activity, as well as kynurenine (KYN), tryptophan (TRP), kynurenic acid (KA), and anthranilic acid (AA) concentrations. The study followed a prospective, longitudinal, single-center cohort design. The severity of the depressive symptoms of 101 adult patients with chronic HCV infections was measured during PEG-IFN-α2a/RBV treatment. We used the Montgomery-Åsberg Depression Rating Scale (MADRS) to assess the severity of depressive symptoms. The subjects were evaluated six times-at baseline and at weeks 2, 4, 8, 12, and 24. At all the time points, MADRS score, as well as KYN, TRP, KA, and AA concentrations, and IDO activity were measured. At baseline, rs6295, rs4570625, and 5-HTTLPR rs25531polymorphisms were assessed. Subjects with C/C genotypes of 5-HT1A and lower-expressing alleles (S/S, LG/LG, and S/LG) of 5-HTTLPR scored the highest total MADRS scores and recorded the highest increase in MADRS scores during treatment. We found associations between TRP concentrations and the TPH-2 and 5-HTTLPR rs25531 genotypes. Our findings provide new data that we believe can help better understand infection-induced depression as a distinct type of depression.

Kynurenine Pathway Activation and Deviation in Fibrosing Chronic Graft-Versus-Host Disease

Background: Fibrosing chronic graft-versus-host disease (cGVHD) is a debilitating complication after allogeneic stem cell transplantation (allo-SCT), and its pathophysiology is poorly understood. Kynurenine and its metabolites were shown to associate with both, interferon-gamma (IFNg) activation and fibrosis. This study investigates the interplay between members of the IFNγ pathway and Kynurenin-derived metabolites in cGVHD.Methods: Using a liquid chromatography tandem mass spectrometry approach on sera obtained on day+100 (n=430) and/or at onset of cGVHD symptoms (n=196) of our prospectively collected biobank after alloSCT, we measured concentrations of Kyn pathway metabolites (kynurenin (Kyn), anthranilic acid (AA), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), and 3-hydroxy-anthranilic acid (3-HAA). We also measured C-X-C chemokine ligand 9 (CXCL9), interleukin (IL-)18, tryptophane (Trp) and indoleamine-2,3-dioxygenase (IDO) by ELISA.Results: We observed increased CXCL9 and IDO levels, and increased activity of the Kynurenine pathway in both non-severe and severe cGVHD. Interestingly, severe fibrosing cGVHD differed from any other form of cGVHD in a significant pathway shift toward AA and KA. This resulted in a reduced 3-HAA/AA ratio. A score consisting of low 3-HAA/AA ratio and high KA serum levels at onset of mild cGVHD symptoms predicted risk specifically of severe fibrosing cGVHD. This altered pathway in severe fibrosing cGVHD correlated with reduced activity of the Vitamin-B2-dependent kynurenine monooxygenase, low vitamin B6, and increased interleukin-18. Our results are consistent with a triple-hit model for fibrosing cGVHD including low activity of kynurenine monooxygenase (KMO, Vitamin B2 and B6 dependent) in the context of high IL18 serum levels and CXCL9-induced IDO activation (Figure 1).Conclusion: Chronic GVHD associates with an IFNg signature and increased activity of the Kynurenin pathway. KA and 3-HAA/AA defined the first molecular distinction between fibrosing and non-fibrosing cGVHD. The mechanism may involve Vitamin B2/B6 deficiency, and high CXCL9 and IL18. The Kyn metabolite signature is a candidate biomarker for severe fibrosing cGHVD and provides a rationale for translational trials on prophylactic Vitamin B2/B6 supplementation for cGVHD prevention.Figure 1: Triple hit model of fibrosing cGVHD (Hypothesis):Severe fibrosing cGVHD associates with a strong CXCL9-induced activation of IDO. The result of this activation is influenced by a reduced activity of kynurenine monooxygenase (KMO), either due to genetic polymorphisms or lack of Vitamin B2, and further aggravated by lack of Vitamin B6. The resulting metabolic deviation increases AA concentrations and reduces the 3-HAA/AA ratio. Finally, high IL-18 associates with increased serum KA. These three hits result in a metabolic situation with high KA and a low ratio 3-HAA/AA that predicts risk of fibrosing cGVHD. [Display omitted] DisclosuresMueller-Tidow: Janssen Cilag: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bioline: Consultancy, Research Funding.

Psychological Stresses in Children Trigger Cytokine- and Kynurenine Metabolite-Mediated Abdominal Pain and Proinflammatory Changes.

Recurrent abdominal pain (RAP) is a common medically unexplained symptom among children worldwide. However, the biological mechanisms behind the development of functional and behavioral symptoms and changes in blood markers have not been well explored. This study aimed to assess changes in the concentrations of inflammatory markers, including cytokines and tryptophan catabolites, in the serum of children with RAP compared to those with subclinical infections. Children with RAP but without organic diseases were included, and those with asymptomatic intestinal parasitic infections were used as a subclinical infection cohort. Blood samples were collected and used to measure the cytokine profile using Multiplex Immunoassay and tryptophan catabolites using high performance liquid chromatography. Children with RAP showed significantly higher concentrations of serum tumor necrotic factor-α, p<0.05, but lower concentrations of IL-10, p<0.001, IL-6, p<0.001 and brain-derived neurotrophic factors (BDNF) p<0.01. In addition, a significant increase in the metabolite of the kynurenine pathway, 3-hydroxyanthranilic acid (3-HAA) p<0.01, a significant decrease in the concentrations of anthranilic acid (AA) p<0.001, together with an increased ratio of serum 3-HAA to AA (3-HAA/AA) p<0.001, was found in this cohort. These findings indicate the significant activation of the immune system and presence of inflammation in children with RAP than those with subclinical parasitic infections. Moreover, children with RAP tested with the Strengths and Difficulties Questionnaire (SDQ), displayed high psychological problems though these SDQ scores were not statistically associated with measured cytokines and kynurenine metabolites. We however could hypothesize that the pro-inflammatory state together with concomitant low concentrations of BDNF in those children with RAP could play a role in psychological stress and experiencing medically unexplained symptoms.

The role of anthranilic acid in the increase of depressive symptoms and major depressive disorder during treatment for hepatitis C with pegylated interferon-α2a and oral ribavirin

BackgroundTryptophan metabolism via the kynurenine pathway is considered the link between the immune and endocrine systems. Dysregulation of serotonergic transmission can stem from the direct influence of interferon-α on the activity of serotonergic receptors 5-HT1A and 5-HT2A, and from its indirect effect on tryptophan metabolism. Induction of the kynurenine pathway increases the concentration of neurotoxic kynurenine metabolites, and the activity of kynurenine derivatives is linked to the onset of depression. The aim of our study was to evaluate the relationships between depressive symptoms and kynurenine, tryptophan, anthranilic acid and kynurenic acid concentrations, indolamine 2,3-dioxygenase (IDO) activity and tryptophan availability to the brain.MethodsThe study followed a prospective longitudinal cohort design. We evaluated 101 patients with chronic hepatitis C who were treated with pegylated interferon-α2a, and 40 controls who were awaiting treatment. We evaluated the relationships between total score on the Montgomery–Åsberg Depression Rating Scale and kynurenine, tryptophan, anthranilic acid and kynurenic acid concentrations, IDO activity and tryptophan availability to the brain. A logistic regression model was adapted for the diagnosis of major depressive disorder at each time point, taking into account changes in parameters of the kynurenine pathway between a given time point and the baseline measurement.ResultsOf the treated patients, 44% fulfilled the criteria for major depressive disorder at least once during the 24 weeks of treatment. Anthranilic acid concentrations were significantly increased compared to baseline for all time points except week 2. Tryptophan availability showed a significant decrease (β = −0.09, p = 0.01) only in week 12 of treatment. Over time, kynurenine, tryptophan and anthranilic acid concentrations, as well as IDO activity and tryptophan availability to the brain, were significantly associated with total score on the Montgomery–Åsberg Depression Rating Scale. A logistic regression model revealed that participants with decreased tryptophan availability to the brain at 12 weeks of treatment and participants with increased anthranilic acid concentrations at week 24 of treatment were at increased risk for diagnosis of major depressive disorder (odds ratios 2.92 and 3.59, respectively).LimitationsThis study had an open-label design in a population receiving naturalistic treatment.ConclusionThe present study provides the first direct evidence of the role of anthranilic acid in the pathogenesis of inflammation-induced major depressive disorder during treatment for hepatitis C with pegylated interferon-α2a.

Probiotic Lactobacillus Plantarum 299v decreases kynurenine concentration and improves cognitive functions in patients with major depression: A double-blind, randomized, placebo controlled study

BackgroundInteractions between the digestive system and the brain functions have become in recent years an important field of psychiatric research. These multidirectional interactions take place in the so called microbiota-gut-brain axis and emerging scientific data indicate to the significant role of microbiota in the modulation of the central nervous system (CNS) including affective and cognitive functions. ObjectiveAn assessment of psychobiotic and immunomodulatory effects of probiotic bacteria Lactobacillus Plantarum 299v (LP299v) by measuring affective, cognitive functions and biochemical parameters in patients with MDD undergoing treatment with selective serotonin reuptake inhibitors (SSRI). DesignSeventy nine patients with MDD were randomized and allocated to a double-blind, placebo-controlled trial. Participants received either a SSRI with the probiotic LP299v (n = 40) for a period of 8 weeks or a SSRI with the placebo of the probiotic (n = 39) for the same period. The severity of psychiatric symptoms was assessed using Hamilton Depression Rating Scale (HAM-D 17), Symptom Checklist (SCL-90) and Perceived Stress Scale (PSS-10). Cognitive functions were assessed using the Attention and Perceptivity Test (APT), Stroop Test parts A and B, Ruff Figural Fluency Test (RFFT), Trail Making Test (TMT) Parts A and B and the California Verbal Learning Test (CVLT). Biochemical parameters such as tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3HKYN), anthranilic acid (AA), 3-hydroxy anthranilic acid (3HAA), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin 1-beta (IL-1b) and cortisol plasma concentrations were measured. ResultsSixty participants finished the study and were analyzed: 30 participants in the LP299v group and 30 participants in the placebo group. There was an improvement in APT and in CVLT total recall of trials 1–5 in the LP299v group compared with the placebo between baseline and after 8 weeks of intervention. There was a significant decrease in KYN concentration in the LP299v group compared to the placebo group. We also observed significant increase in 3HKYN:KYN ratio in the LP299v group compared with the placebo group. Additionally, Repeated Measures ANOVA revealed a significant effect of interaction of Treatment x time for AA concentration. However, results of post hoc analysis did not reach statistical significance in neither probiotic nor placebo group. There were no significant changes of TNF-α, IL-6 and IL-1b and cortisol concentrations in neither probiotic nor placebo groups. ConclusionsAugmentation of SSRI treatment with probiotic bacteria Lactobacillus Plantarum 299v improved cognitive performance and decreased KYN concentration in MDD patients. Decreased KYN concentration could contribute to the improvement of cognitive functions in the LP299v group compared to the placebo group. To our knowledge results of this study are the first evidence of improvement of cognitive functions in MDD patients due to probiotic bacteria and this is the first evidence of decreased KYN concentration in MDD patients due to probiotic bacteria.

Poster #S206 VITAMIN D DEFICIENCY IN DUTCH OUTPATIENTS WITH BIPOLAR DISORDER, SCHIZOAFFECTIVE DISORDER OR SCHIZOPHRENIA

Interactions between the digestive system and the brain functions have become in recent years an important field of psychiatric research. These multidirectional interactions take place in the so called microbiota-gut-brain axis and emerging scientific data indicate to the significant role of microbiota in the modulation of the central nervous system (CNS) including affective and cognitive functions.An assessment of psychobiotic and immunomodulatory effects of probiotic bacteria Lactobacillus Plantarum 299v (LP299v) by measuring affective, cognitive functions and biochemical parameters in patients with MDD undergoing treatment with selective serotonin reuptake inhibitors (SSRI).Seventy nine patients with MDD were randomized and allocated to a double-blind, placebo-controlled trial. Participants received either a SSRI with the probiotic LP299v (n = 40) for a period of 8 weeks or a SSRI with the placebo of the probiotic (n = 39) for the same period. The severity of psychiatric symptoms was assessed using Hamilton Depression Rating Scale (HAM-D 17), Symptom Checklist (SCL-90) and Perceived Stress Scale (PSS-10). Cognitive functions were assessed using the Attention and Perceptivity Test (APT), Stroop Test parts A and B, Ruff Figural Fluency Test (RFFT), Trail Making Test (TMT) Parts A and B and the California Verbal Learning Test (CVLT). Biochemical parameters such as tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3HKYN), anthranilic acid (AA), 3-hydroxy anthranilic acid (3HAA), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin 1-beta (IL-1b) and cortisol plasma concentrations were measured.Sixty participants finished the study and were analyzed: 30 participants in the LP299v group and 30 participants in the placebo group. There was an improvement in APT and in CVLT total recall of trials 1–5 in the LP299v group compared with the placebo between baseline and after 8 weeks of intervention. There was a significant decrease in KYN concentration in the LP299v group compared to the placebo group. We also observed significant increase in 3HKYN:KYN ratio in the LP299v group compared with the placebo group. Additionally, Repeated Measures ANOVA revealed a significant effect of interaction of Treatment x time for AA concentration. However, results of post hoc analysis did not reach statistical significance in neither probiotic nor placebo group. There were no significant changes of TNF-α, IL-6 and IL-1b and cortisol concentrations in neither probiotic nor placebo groups.Augmentation of SSRI treatment with probiotic bacteria Lactobacillus Plantarum 299v improved cognitive performance and decreased KYN concentration in MDD patients. Decreased KYN concentration could contribute to the improvement of cognitive functions in the LP299v group compared to the placebo group. To our knowledge results of this study are the first evidence of improvement of cognitive functions in MDD patients due to probiotic bacteria and this is the first evidence of decreased KYN concentration in MDD patients due to probiotic bacteria.

3-hydroxyanthranilic acid is independently associated with monocyte chemoattractant protein-1 (CCL2) and macrophage inflammatory protein-1β (CCL4) in patients with chronic kidney disease

Objectives CC-chemokines and kynurenine pathway (KP) metabolites are associated with accelerated atherosclerosis in chronic kidney disease (CKD) patients. Design and methods We evaluate the plasma levels of anthranilic acid (AA), 3-hydroxyanthranilic acid (3-HAA) and their possible relationship with CC-chemokines, Cu/Zn superoxide dismutase (Cu/Zn SOD) as the marker of oxidative status and high sensitivity C-reactive protein (hsCRP) as an index of inflammation in the population of 48 CKD patients. Results Compared with controls, CKD patients showed a significant increase in plasma concentrations of CCL2, CCL4, AA, 3-HAA, Cu/Zn SOD and hsCRP. Multiple stepwise regression analysis identified inflammation, renal function and 3-HAA levels as the independent variables significantly associated with increased CCL2; whereas age, 3-HAA and renal function as independent variables associated with CCL4. Conclusions These results suggest a relationship between CC-chemokine system and KP activation, which may represent one of the mechanisms involved in the accelerated atherosclerosis in CKD population.

Kynurenine and Its Metabolites—Kynurenic Acid and Anthranilic Acid are Associated With Soluble Endothelial Adhesion Molecules and Oxidative Status in Patients With Chronic Kidney Disease

BackgroundCellular adhesion molecules and oxidative stress play a role in the pathogenesis of atherosclerosis in patients with chronic kidney disease (CKD). Recently, it has been postulated that the kynurenine (KYN) pathway could be involved in the pathogenesis of atherosclerosis. MethodsWe evaluated the KYN, kynurenic acid (KYNA), anthranilic acid (AA), and their relations with cellular adhesion molecules: soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), sE-selectin, sP-selectin, and Cu/Zn superoxide dismutase (Cu/Zn SOD) levels as the markers of oxidative stress in the population of 132 patients with CKD and 28 healthy controls. ResultsCompared with the controls, 2 groups of dialyzed patients had significantly increased KYN (both P<0.01), KYNA, AA, sICAM-1, sVCAM-1, and Cu/Zn SOD levels (all P<0.001, respectively). KYN, AA, sICAM-1, and sVCAM-1 concentrations were significantly higher in undialyzed patients with CKD compared with healthy subjects (P<0.001, P<0.01, and both P<0.05, respectively). sICAM-1 and sVCAM-1 were positively associated with KYN (P<0.0001 and P<0.01), KYNA (P<0.05 and P<0.0001), AA (P<0.01 and P<0.0001), and with Cu/Zn SOD (both P<0.0001, respectively) in the whole CKD group. The positive relationship existed between sICAM-1, sVCAM-1 and age, high-sensitivity C-reactive protein, creatinine, and the duration of dialysis therapy. Multivariable analysis showed that KYN was a strong independent correlate of sICAM-1, whereas Cu/Zn SOD and platelets independently and significantly predicted sVCAM-1 in patients with CKD. ConclusionsThis study demonstrated that KYN is independently and significantly associated with elevated sICAM-1, whereas oxidative status and platelets independently and significantly predicted increased sVCAM-1 levels in patients with CKD.

P.3.b.008 N-acetylcysteine prevents prenatal poly I:C-induced disruption of latent inhibition and increase in tyrosine hydroxylase

Anthranilic acid (AA) has attracted considerable attention as one of thel-tryptophan–kynurenine pathway metabolites in the central nervous system. In this study, a highly sensitive and accurate method for the quantification of AA has been developed using reversed-phase high-performance liquid chromatography with electrochemical detection. Serum and cerebrospinal fluid (CSF) AA concentrations in different animal species were measured. CSF AA concentrations in rabbits were 1.1 ± 0.1 nmol/liter, which were 5.7–33.0 times lower than those in other species studied. Serum AA concentrations, however, were slightly higher in rabbits than in other species. In contrast, the concentrations ofl-kynurenine (L-KYN) in both serum and CSF were substantially higher in rabbits than in other species. Tissue kynurenine pathway enzymes, indoleamine 2,3-dioxygenase (IDO), tryptophan 2,3-dioxygenase, kynurenine 3-hydroxylase, and kynureninase were determined in rabbits, rats, gerbils, and mice. These enzymes varied among species, especially lung IDO activities in rabbits were 146–516 times higher than those found in other species, but rabbit liver kynurenine 3-hydroxylase activities were lower by one order of magnitude than those of the other species tested. Furthermore, brain kynurenine 3-hydroxylasae activities were 12.3–23.2 times higher in gerbils than those in the other species tested. In addition, AA concentrations in serum following intravenous administration of L-KYN (5 mg/kg) were also measured in rabbits. AA levels peaked sharply within 5 min after administration and decreased in a time-dependent manner. At 5 min after administration, CSF L-KYN and AA concentrations were also increased by 1.76- and 2.56-fold, respectively, compared with basal levels. Increased AA concentrations in CSF following L-KYN administration may reflect the entry of AA into the CSF after conversion to AA in systemic tissue and/or the local synthesis of AA from L-KYN in the CNS.

Anthranilic Acid–uraemic Toxin Damaged Red Cell’s Membrane

Normocytic normochromic anaemia is a common syndrome present in patients with chronic renal insufficiency (CRI). Simultaneously in these patients the increase in L-tryptophan (TRP) degradation via kynurenine pathway is observed. On the basis of these observations we tried to examine whether one of the TRP metabolites, anthranilic acid (AA), shows interaction with membranes of erythrocytes and because of that it may contribute to anaemia development. In patients with CRI we have observed changes characteristic for normocytic normochromic anaemia, such as the decrease in erythrocyte count, haemoglobin concentration, haematocrit and the decrease in erythrocyte osmotic resistance as well as the increase in AA concentration in plasma in comparison to healthy subjects. We have also noticed the existence of a positive correlation between anthranilic acid concentration and creatinine and urea concentrations and also negative relationships between anthranilic acid concentration and haematological parameters. Moreover, incubation of healthy erythrocytes with 10 and 100 microM AA caused haemolysis curve movement to the right, which shows decrease in osmotic resistance. In conclusion, the increase in plasma AA concentration might be one of many factors, which damage erythrocyte membrane, and thereby contributes to anaemia development in patients with CRI.

In situ UV–visible spectroelectrochemical studies on the copolymerization of diphenylamine with anthranilic acid

In situ spectroelectrochemical studies were carried out on the polymerization of diphenylamine (DPA) and copolymerization of DPA with anthranilic acid (AA). Electropolymerization was performed in aqueous 2 M H 2SO 4 by applying a constant potential (0.80 V) on indium tin oxide (ITO)-coated glass electrode. Spectral characteristics were followed for various feed ratios of the comonomers (DPA and AA) at different polymerization times. Two types of cation radicals could be observed for the electropolymerization with mixture of DPA and AA, corresponding to anilinium-type and N, N′-diphenylbenzidine-type, respectively. UV–visible spectra recorded for copolymerization inform that the peak position corresponding to DPB + showed clear dependence on AA concentration in the feed, signifying the changes in the overall oxidation states of the polymer as a result of incorporation of AA units in the copolymer. The FTIR spectral analysis of the copolymer clearly reveals the incorporation of AA units into the polymer backbone during polymerization. The presence of a band at 1650 cm −1 in FTIR spectra corresponding to the –CO group of AA units and the improvement in thermal stability of the copolymer as observed from thermogravimetric analysis (TGA) favor the incorporation of AA units in the copolymer.

Electrochemical Copolymerization of Diphenylamine and Anthranilic Acid with Various Feed Ratios

Electrochemical copolymerization of diphenylamine (DPA) with anthranilic acid (AA) was performed in aqueous 4 M solution for different feed ratios of DPA using cyclic voltammetry. The copolymer film was grown for different numbers of cycles, and feed ratios of DPA. Electrochemical homopolymerization of DPA was also carried out under identical conditions and compared. A growth equation of the deposited films in terms of concentrations of DPA and AA and is deduced as by utilizing the charge associated for film deposition. The copolymer compositions were determined by X-ray photoelectron spectroscopy. Reactivity ratios of DPA and AA were computed by using Fineman-Ross and Kelen-Tüdös methods. © 2001 The Electrochemical Society. All rights reserved.

Changes in kynurenic, anthranilic, and quinolinic acid concentrations in rat brain tissue during development.

Kynurenic, anthranilic, and quinolinic acid, brain tissue concentrations and indoleamine 2,3-dioxygenase [EC 1 13.11.17] activity were determined in rat brain, during pre- and postnatal development. Quinolinic acid brain tissue concentration was significantly increased at birth as compared with the prenatal level, then it declined rapidly in the postnatal period. By the contrary, kynurenic and anthranilic acids brain tissue concentrations in rat brain were significantly lower at birth as compared with those found prenatally; then kynurenic acid concentration decreased in the first postnatal week and increased thereafter, while anthranilic acid concentration increased in the first postnatal week and decreased thereafter. Indoleamine 2,3-dioxygenase [EC 1 13.11.17] activity were found unchanged in pre and post natal rat brain. The described opposite changes in quinolinic and kynurenic acids concentrations, occurring in pre- and postnatal period, despite the lack of knowledge on the precise role played by these compounds on the different neurotransmitter systems in the brain, could be involved in brain ontogenetic development.

Evidence that kynurenine pathway metabolites mediate hyperbaric oxygen-induced convulsions

Metabolism of tryptophan (TRP) through the kynurenine (KYN) pathway in brain, liver, and kidney produces intermediates including the neuroactive agonist quinolinic acid (QA) and the antagonists kynurenic acid (KA) and anthranilic acid (AA) for N-methyl d-aspartate (NMDA) receptors in the central nervous system. We hypothesized that elevated concentrations of QA, KA, or AA can moderate the convulsions that are observed during exposure of rats to hyperbaric oxygen (HBO). We found that i.p. administration of TRP or KYN (both of which cross the blood-brain barrier) had no effect on HBO-induced seizures. However, AA (administered i.p.) or gavage administration of the KYN pathway blocking drug Ro 61-8048, both of which enter the brain from the circulatory system, affect the time to first convulsion and/or coma during HBO in a manner consistent with a modulatory role for seizure activity.

Species Differences inl-Tryptophan–Kynurenine Pathway Metabolism: Quantification of Anthranilic Acid and Its Related Enzymes

Anthranilic acid (AA) has attracted considerable attention as one of thel-tryptophan–kynurenine pathway metabolites in the central nervous system. In this study, a highly sensitive and accurate method for the quantification of AA has been developed using reversed-phase high-performance liquid chromatography with electrochemical detection. Serum and cerebrospinal fluid (CSF) AA concentrations in different animal species were measured. CSF AA concentrations in rabbits were 1.1 ± 0.1 nmol/liter, which were 5.7–33.0 times lower than those in other species studied. Serum AA concentrations, however, were slightly higher in rabbits than in other species. In contrast, the concentrations ofl-kynurenine (L-KYN) in both serum and CSF were substantially higher in rabbits than in other species. Tissue kynurenine pathway enzymes, indoleamine 2,3-dioxygenase (IDO), tryptophan 2,3-dioxygenase, kynurenine 3-hydroxylase, and kynureninase were determined in rabbits, rats, gerbils, and mice. These enzymes varied among species, especially lung IDO activities in rabbits were 146–516 times higher than those found in other species, but rabbit liver kynurenine 3-hydroxylase activities were lower by one order of magnitude than those of the other species tested. Furthermore, brain kynurenine 3-hydroxylasae activities were 12.3–23.2 times higher in gerbils than those in the other species tested. In addition, AA concentrations in serum following intravenous administration of L-KYN (5 mg/kg) were also measured in rabbits. AA levels peaked sharply within 5 min after administration and decreased in a time-dependent manner. At 5 min after administration, CSF L-KYN and AA concentrations were also increased by 1.76- and 2.56-fold, respectively, compared with basal levels. Increased AA concentrations in CSF following L-KYN administration may reflect the entry of AA into the CSF after conversion to AA in systemic tissue and/or the local synthesis of AA from L-KYN in the CNS.

Regulation of enzymes of the kynurenine pathway by interferon-gamma in murine macrophages and microglia

Anthranilic acid (AA) has attracted considerable attention as one of thel-tryptophan–kynurenine pathway metabolites in the central nervous system. In this study, a highly sensitive and accurate method for the quantification of AA has been developed using reversed-phase high-performance liquid chromatography with electrochemical detection. Serum and cerebrospinal fluid (CSF) AA concentrations in different animal species were measured. CSF AA concentrations in rabbits were 1.1 ± 0.1 nmol/liter, which were 5.7–33.0 times lower than those in other species studied. Serum AA concentrations, however, were slightly higher in rabbits than in other species. In contrast, the concentrations ofl-kynurenine (L-KYN) in both serum and CSF were substantially higher in rabbits than in other species. Tissue kynurenine pathway enzymes, indoleamine 2,3-dioxygenase (IDO), tryptophan 2,3-dioxygenase, kynurenine 3-hydroxylase, and kynureninase were determined in rabbits, rats, gerbils, and mice. These enzymes varied among species, especially lung IDO activities in rabbits were 146–516 times higher than those found in other species, but rabbit liver kynurenine 3-hydroxylase activities were lower by one order of magnitude than those of the other species tested. Furthermore, brain kynurenine 3-hydroxylasae activities were 12.3–23.2 times higher in gerbils than those in the other species tested. In addition, AA concentrations in serum following intravenous administration of L-KYN (5 mg/kg) were also measured in rabbits. AA levels peaked sharply within 5 min after administration and decreased in a time-dependent manner. At 5 min after administration, CSF L-KYN and AA concentrations were also increased by 1.76- and 2.56-fold, respectively, compared with basal levels. Increased AA concentrations in CSF following L-KYN administration may reflect the entry of AA into the CSF after conversion to AA in systemic tissue and/or the local synthesis of AA from L-KYN in the CNS.

Effect of athranilic aid on the gowth of bue-geen agae

Effect of anthranilic acid concentrations (10 −10 –10 −3 M) on the growth of Anacystis nidulans and Tolypothrix tenuis , under aseptic conditions, has been described. Anthranilic acid promoted the growth of T. tenuis at the concentrations of 10 −10 –10 −6 M whereas it failed to stimulate the growth of A. nidulans .

Biosynthesis of dictamnine. The origin of the quinoline nucleus

The biosynthesis of dictamnine, a furoquinoline alkaloid, was studied in intact Dictamnus albus plants. The quinoline ring system is derived from anthranilic acid and acetate. Tryptophan is not a precursor. Anthranilic acid concentration appears to control the rate of dictamnine biosynthesis in intact D. albus.