Search

Aim    To compare serum concentrations of tryptophane (Trp) and its metabolites in subjects with no cardiovascular disease (CVD) and patients with СVD, including arterial hypertension (AH) and ischemic heart disease (IHD).Material and methods    This study included 131 participants; 58 participants (11 of them with documented peripheral atherosclerosis) were included into the AH group, 46 participants were included into the IHD group, and 27 participants with no signs of CVD were included into the control group. Plasma concentrations of Trp and its metabolites were measured by high-performance liquid chromatography in combination with a triple quadrupole analyzer.Results    Comparison of the three study groups revealed significant differences in concentrations of Trp (р=0.029), kynurenine (p<0.001), kynurenine/Trp ratio (p<0.001), quinolinic acid (р=0.007), kynurenic acid (р=0.003), serotonin (p<0.001), and 5‑hydroxyindoleacetic acid (5‑HIAA) (р=0.011). When the AH group was subdivided into subgroups without and with documented peripheral atherosclerosis, the intergroup differences remained for concentrations of kynurenine, kynurenine/Trp ratio, quinolinic acid, kynurenic acid, serotonin, and 5‑HIAA. Also, correlations were found between concentrations of Trp metabolites and laboratory and instrumental data, primarily inflammatory markers. Conclusion    Analysis of serum concentrations of Trp and its metabolites in CVD patients showed increases in kynurenine, kynurenine/Trp ratio, quinolinic acid, kynurenic acid, and 5‑HIAA along with decreases in concentrations of Trp and serotonin in the groups of AH, AH with documented peripheral atherosclerosis, and IHD.

Objective: Neurotoxic metabolites of the kynurenine pathway are thought to be implicated in the pathogenesis of schizophrenia. The enzyme indoleamine 2,3-dioxygenase (IDO) catalyzes the initial step of the kynurenine pathway that converts tryptophan to kynurenine metabolites. IDO is induced by proinflammatory cytokines. We studied IL-1Β T-511C (rs16944), IL-1Β C3954T (rs1143634), IDO VNTR and IDO rs9657182 polymorphisms in patients with schizophrenia and controls., Material and Methods: Genotyping was performed in 296 patients with schizophrenia (ICD-10 F20.0) and 355 healthy controls., Results: The multiple dimension reduction (MDR) analysis revealed a combination included alleles С (T-511C), Т (C3954T), V1 (VNTR) and С (rs9657182), which was associated with schizophrenia (OR 3,3 CI 95% 2,3-4,8)., Conclusion: This is the first report of the interaction between IL-1Β and IDO genes. Further research into genes of the kynurenine pathway is needed.

The essential amino acid tryptophan is metabolized on the methoxyindole pathway to serotonin, melatonin and 5-hydroxyindoleacetic acid and on the kynurenine pathway to kynurenine and related neuroactive metabolites, including 3-hydroxykynurenine, kynurenic acid, quinolinic acid and xanthurenic acid. Kynurenine and related metabolites play a significant role in the pathogenesis of major depressive disorder and schizophrenia. This paper is the review of literature data on the most modern state of this problem.

The resistance of courtship behavior and communicative sound production to heat shock (37 degrees C, 30 min) was studied in wild-type Canton S (CS) male Drosophila melanogaster and males of two strains with defects in the kynurenine pathway of tryptophan metabolism (KPTM) caused by mutations cinnabar (block at the level of kynurenine-3-hydroxylase leading to accumulation of kynurenic acid, a neuroprotective metabolite, in the brain) and cardinal (block at the level of phenoxazinone synthetase causing accumulation of 3-hydroxykynurenine, an oxidative stress generator, in the brain). Males of each strain were divided into four groups. Males from control groups were not exposed to heat shock. The other groups were exposed to heat shock at the late embryonic/early larval (the first instar) developmental stage, when mushroom bodies are formed (HS1 groups); at the prepupal stage, when the brain central complex develops (HS2 groups); or at the imago stage 1 h before the experiment (HS groups). All males were tested at an age of five days. Virgin and fertilized five-day-old CS females served as courtship objects. The courtship behavior and singing of control CS and cinnabar males were similar. Control cardinal males also had high motivation, but their courtship efficiency was lower because of less precise movements (wing vibration was often not accompanied by sound production) and hyperexcitability. Exposure of first-instar larvae to heat shock had almost no effect on behavior or singing of adult males of any strain. In cardinal males exposed to heat shock at the prepupal stage or, especially, at the imago stage 1 h before the test (the HS2 and HS groups), courtship was strongly impaired, and various distortions appeared in their sound signals, which indicated disturbance of coordination between elements of the song center and their interaction with pacemakers. These effects were much milder or absent altogether in HS2 and HS wild-type males and, especially, cinnabar males. Thus, permanent excess of 3-hydroxykynurenine in the male brain dramatically decreased their stress resistance. In contrast, excess of kynurenic acid alleviated the consequences of stress.

Methods of immunohistochemistry and fluorescent staining was used to study the localization and amounts of protein components of the signal cascade connecting the receptor link (NMDA-subtype glutamate receptor) with actin of the cytoskeleton in the head ganglia of Drosophila strain Canton-S (wild type, control) and strains carrying mutations vermilion, cinnabar, and cardinal, which sequentially inactivate tryptophan-hydrolyzing enzymes during its metabolism into ommochrome. The obtained data are evidence for modulatory effects of genes controlling the kynurenine pathway of tryptophan metabolism on the major components of the signal cascade: the initial link (NMDA receptor, postsynaptic density protein-95, a structural protein involved in receptor localization and internalization), the intermediate link (limkinase-l, the key neuronal enzyme in actin remodeling) and the final link (f-actin, the critical factor in the morphogenesis of synaptic structures and, hence, in the processes of synaptic plasticity, learning and memory). It is suggested that kynurenine acid (an endogenous nonspecific antagonist of L-glutamate receptor) and 3-hydroxykynurenine capable of inducing a nonspecific stimulating effect are biochemical intermediates of the effects of these genes.

One out of six trytophan residues in two lysozyme modification, obtained under lysozyme photooxidation in the presence of methylene blue, is found to be oxidized to N'-formylkinurenine (in one modification) and to kinurenine (in the other modification). The transition of one modification into another via detaching of N'-formyl group by soft acid hydrolysis has shown that one and the same tryptophan residue is oxidized in both products, Possible mechanism of tryptophan oxidation to the products mentioned is discu-sed on the basis of the hypothesis on signlet mechanism of lysozyme photooxidation in the presence of methylene blue.

Isolated thoracic ganglia were incubated in physiological solution containing 14C-tryptophan. After this procedure, they were homogenized in a 1 per cent solution of HCL in methanol, and supernatant was subjected to two-dimensional thin layer chromatography in the presence of tryptophan, kynurenine, 3-hydroxy kynurenine, as well as kynurenic, anthranilic and xanthurenic acids. The spots were cut out and counted by liquid scintillation technique. Except tryptophan, only kynurenine and 3-hydroxy kynurenine spots contained notable radioactivity. Therefore, at least the initial stages of kynurenine pathway operate in the nervous system of Drosophila melanogaster. This finding is in accordance with observations of the effects of kynurenines on insect behaviour.