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Inseyah Bagasrawala, Nada Zecevic, Nevena V Radonjić
Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan degradation, acts as an endogenous N-methyl-D-aspartate receptor (NMDAR) antagonist. Elevated levels of KYNA have been observed in pregnant women after viral infections and are considered to play a role in neurodevelopmental disorders. However, the consequences of KYNA-induced NMDAR blockade in human cortical development still remain elusive. To study the potential impact of KYNA on human neurodevelopment, we used an in vitro system of multipotent cortical progenitors, i...
2016: Frontiers in Neuroscience
G Oxenkrug, J Cornicelli, M van der Hart, J Roeser, P Summergrad
Obesity is an increasingly urgent global problem and the molecular mechanisms of obesity are not fully understood. Dysregulation of the tryptophan (Trp) - kynurenine (Kyn) metabolic pathway (TKP) have been suggested as a mechanism of obesity and described in obese humans and in animal models of obesity. However, to the best of our knowledge, TKP metabolism has not been studied in leptin-receptor-deficient Zucker fatty rats (ZFR) (fa/fa), the best-known and most widely used rat model of obesity. We were interested to determine if there are any deviations of TKP in ZFR...
2016: Integrative Molecular Medicine
H Zhao, J Shen, D Djukovic, C Daniel-MacDougall, H Gu, X Wu, W-H Chow
OBJECTIVE: Obesity is a metabolic disease. However, the underlying molecular mechanisms linking metabolic profiles and weight gain are largely unknown. METHODS: Here, we used semi-targeted metabolomics to assay 156 metabolites selected from 25 key metabolic pathways in plasma samples from 300 non-smoking healthy women identified from Mano-A-Mano, the Mexican American Cohort study. The study subjects were randomly divided into two cohorts: training (N = 200) and testing (N = 100) cohorts...
September 2016: Obesity Science & Practice
Tatiane da Silva Araújo, Adriano Jose Maia Chaves Filho, Aline Santos Monte, Ana Isabelle de Góis Queiroz, Rafaela Carneiro Cordeiro, Michel de Jesus Souza Machado, Ricardo de Freitas Lima, David Freitas de Lucena, Michael Maes, Danielle Macêdo
Immune dysregulation observed in schizophrenia alters tryptophan metabolism. Tryptophan metabolism is triggered by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Tryptophan is converted to quinolinic acid, a potent neurotoxin, and to kynurenic acid, an NMDA antagonist. 1-Methyl-D-tryptophan (MDT) inhibits IDO. Melatonin is metabolized by IDO while inhibiting TDO. We evaluated the reversal of ketamine-induced schizophrenia-like behavioral and neurochemical alterations in mice by the administration of MDT (20 or 40 mg/kg, i...
September 21, 2016: Journal of Psychiatric Research
Tomoyuki Tashiro, Yuki Murakami, Akihiro Mouri, Yukio Imamura, Toshitaka Nabeshima, Yasuko Yamamoto, Kuniaki Saito
l-Tryptophan (TRP) is metabolized via serotonin and kynurenine pathways (KP). Several studies have demonstrated that abnormality of both pathways is involved in the pathogenesis of major depressive disorder (MDD). Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the KP, has been suggested to play major roles in physiological and pathological events mediated by bioactive kynurenine metabolites. In this study, we investigated the role of KMO in the emotional and cognitive functions by using KMO knockout (KO) mice...
September 28, 2016: Behavioural Brain Research
E Kaczorek, J Szarek, M Mikiewicz, E Terech-Majewska, P Schulz, J Małaczewska, R Wójcik, A K Siwicki
Kynurenic acid (KYNA) is an endogenous substance produced on the kynurenine pathway which is primarily known for its neuroactive properties. Recently, it has been proven that KYNA is a selective ligand for G protein-coupled receptor (GPR 35), presented on immunocompetent cells such as T lymphocytes. This opens up new possibilities of its application as an immunostimulating substance in aquaculture. Thus far, no histopathological investigations in fish have been completed to evaluate influence of KYNA supplementation in feed...
September 30, 2016: Journal of Fish Diseases
Jenni Puurunen, Sini Sulkama, Katriina Tiira, Cesar Araujo, Marko Lehtonen, Kati Hanhineva, Hannes Lohi
BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a prevalent and multifactorial neuropsychiatric disorder in the human population worldwide. Complex etiology and clinical heterogeneity have challenged the research, diagnostics and treatment of the disease. Hyperactive and impulsive behaviour has also been observed in dogs, and they could offer a physiologically relevant model for human ADHD. As a part of our ongoing study to understand the molecular etiology of canine anxiety traits, this study was aimed to pilot an approach to identify metabolic biomarkers in canine ADHD-like behaviours for research, diagnostics and treatment purposes...
September 29, 2016: Behavioral and Brain Functions: BBF
Gábor Veres, Annamária Fejes-Szabó, Dénes Zádori, Gábor Nagy-Grócz, Anna M László, Attila Bajtai, István Mándity, Márton Szentirmai, Zsuzsanna Bohár, Klaudia Laborc, István Szatmári, Ferenc Fülöp, László Vécsei, Árpád Párdutz
Kynurenic acid (KYNA) has well-established protective properties against glutamatergic neurotransmission, which plays an essential role in the activation and sensitization process during some primary headache disorders. The goal of this study was to compare the effects of two KYNA analogs, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KA-1) and N-(2-N-pyrrolidinylethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KA-2), in the orofacial formalin test of trigeminal pain. Following pretreatment with KA-1 or KA-2, rats were injected with subcutaneous formalin solution in the right whisker pad...
September 14, 2016: Journal of Neural Transmission
Caroline M Forrest, Peter G E Kennedy, Jean Rodgers, R Neil Dalton, Charles Turner, L Gail Darlington, Stuart R Cobb, Trevor W Stone
To quantify the full range of tryptophan metabolites along the kynurenine pathway, a liquid chromatography - tandem mass spectrometry method was developed and used to analyse brain extracts of rodents treated with the kynurenine-3-mono-oxygenase (KMO) inhibitor Ro61-8048 during pregnancy. There were significant increases in the levels of kynurenine, kynurenic acid, anthranilic acid and 3-hydroxy-kynurenine (3-HK) in the maternal brain after 5 h but not 24 h, while the embryos exhibited high levels of kynurenine, kynurenic acid and anthranilic acid after 5 h which were maintained at 24 h post-treatment...
September 10, 2016: Neurochemistry International
Sara Poletti, Aye Mu Myint, Gregor Schüetze, Irene Bollettini, Elena Mazza, Doris Grillitsch, Clara Locatelli, Markus Schwarz, Cristina Colombo, Francesco Benedetti
Decreased availability of serotonin in the central nervous system has been suggested to be a central factor in the pathogenesis of depression. Activation of indoleamine 2-3 dioxygenase following a pro-inflammatory state could reduce the amount of tryptophan converted to serotonin and increase the production of tryptophan catabolites such as kynurenic acid, an antagonist of ionotropic excitatory aminoacid receptors, whose levels are reduced in bipolar disorder. Abnormalities in white matter (WM) integrity have been widely reported in BD...
September 12, 2016: European Archives of Psychiatry and Clinical Neuroscience
Timothy B Meier, Melissa A Lancaster, Andrew R Mayer, T Kent Teague, Jonathan Savitz
There is a great need to identify potential long-term consequences of contact sport exposure and to identify molecular pathways that may be associated with these changes. We tested the hypothesis that football players with (Ath-mTBI) (n = 25) and without a concussion history (Ath) (n = 24) have altered resting state functional connectivity in regions with previously documented structural changes relative to healthy controls without football or concussion history (HC) (n = 27). As a secondary aim, we tested the hypothesis that group differences in functional connectivity are moderated by the relative ratio of neuroprotective to neurotoxic metabolites of the kynurenine pathway...
October 13, 2016: Journal of Neurotrauma
Funda Orhan, Maria Bhat, Kristian Sandberg, Sara Ståhl, Fredrik Piehl, Camilla Svensson, Sophie Erhardt, Lilly Schwieler
Tryptophan degradation along the kynurenine pathway is of central importance for the immune function. Toll-like receptors (TLRs), representing the first line of immune defense against pathogens, are expressed in various cell types. The most abundant expression is found on monocytes, macrophages and dendritic cells. The aim of the present study is to investigate if stimulation with different TLR ligands induces the kynurenine pathway in human peripheral monocytes. Cell supernatants were analyzed using a liquid chromatography/mass spectrometry to measure kynurenine, kynurenic acid (KYNA), quinolinic acid (QUIN) and tryptophan...
September 8, 2016: Scandinavian Journal of Immunology
Joanne H Huang, Shaunna S Berkovitch, Jonathan Iaconelli, Bradley Watmuff, Hyoungjun Park, Shrikanta Chattopadhyay, Donna McPhie, Dost Öngür, Bruce M Cohen, Clary B Clish, Rakesh Karmacharya
Many studies suggest the presence of aberrations in cellular metabolism in bipolar disorder. We studied the metabolome in bipolar disorder to gain insight into cellular pathways that may be dysregulated in bipolar disorder and to discover evidence of novel biomarkers. We measured polar and nonpolar metabolites in fibroblasts from subjects with bipolar I disorder and matched healthy control subjects, under normal conditions and with two physiologic perturbations: low-glucose media and exposure to the stress-mediating hormone dexamethasone...
July 2016: Molecular Neuropsychiatry
Margaret Lois Thomas, Roberto de Antueno, Krysta Mila Coyle, Mohammad Sultan, Brianne Marie Cruickshank, Michael Anthony Giacomantonio, Carman Anthony Giacomantonio, Roy Duncan, Paola Marcato
Breast cancer stem cells (CSCs) can be identified by increased Aldefluor fluorescence caused by increased expression of aldehyde dehydrogenase 1A3 (ALDH1A3), as well as ALDH1A1 and ALDH2. In addition to being a CSC marker, ALDH1A3 regulates gene expression via retinoic acid (RA) signaling and plays a key role in the progression and chemotherapy resistance of cancer. Therefore, ALDH1A3 represents a druggable anti-cancer target of interest. Since to date, there are no characterized ALDH1A3 isoform inhibitors, drugs that were previously described as inhibiting the activity of other ALDH isoforms were tested for anti-ALDH1A3 activity...
November 2016: Molecular Oncology
Li-Jun Hu, Xiao-Fang Li, Jin-Qing Hu, Xiao-Jia Ni, Hao-Yang Lu, Jia-Jia Wang, Xiang-Ning Huang, Chao-Xian Lin, De-Wei Shang, Yu-Guan Wen
The kynurenine pathway, in which tryptophan is metabolized to kynurenine and kynurenic acid, has been linked to depression. A rapid and highly reproducible liquid-chromatography-tandem mass spectrometry (LC-MS/MS) method were established for determining tryptophan, kynurenine and kynurenic acid in human serum. Biological samples were precipitated with methanol before separation on an Agilent Eclipse XDB-C18. The stable-isotope-labeled internal standards (kynurenine-(13)C4 (15)N and kynurenic acid-d5) were used for quantification...
September 1, 2016: Journal of Analytical Toxicology
Kathrin D Gensberger, Anna-Kristin Kaufmann, Haike Dietrich, Francisco Branoner, Roberto Banchi, Boris P Chagnaud, Hans Straka
UNLABELLED: Galvanic vestibular stimulation (GVS) uses modulated currents to evoke neuronal activity in vestibular endorgans in the absence of head motion. GVS is typically used for a characterization of vestibular pathologies; for studies on the vestibular influence of gaze, posture, and locomotion; and for deciphering the sensory-motor transformation underlying these behaviors. At variance with the widespread use of this method, basic aspects such as the activated cellular substrate at the sensory periphery or the comparability to motion-induced neuronal activity patterns are still disputed...
August 31, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Judit Herédi, Anikó Magyariné Berkó, Ferenc Jankovics, Tokuko Iwamori, Naoki Iwamori, Etsuro Ono, Szatmár Horváth, Zsolt Kis, József Toldi, László Vécsei, Levente Gellért
During catabolism of tryptophan through the kynurenine (KYN) pathway, several endogenous metabolites with neuromodulatory properties are produced, of which kynurenic acid (KYNA) is one of the highest significance. The causal role of altered KYNA production has been described in several neurodegenerative and neuropsychiatric disorders (e.g., Parkinson's disease, Huntington's disease, schizophrenia) and therefore kynurenergic manipulation with the aim of therapy has recently been proposed. Conventionally, KYNA is produced from its precursor L-KYN with the aid of the astrocytic kynurenine aminotransferase-2 (KAT-2) in the murine brain...
August 27, 2016: Brain Structure & Function
Joerg C Schefold, Nora Fritschi, Gerhard Fusch, Aldin Bahonjic, Wolfram Doehner, Stephan von Haehling, Rene Pschowski, Christian Storm, Tim Schroeder
BACKGROUND/AIMS: Temperature control improves neurological prognosis in comatose cardiac arrest (CA) survivors. Previous reports demonstrate that most affected patients show signs of significant systemic inflammation. In an effort to better characterize potential temperature-related effects on key inflammatory pathways, we investigate the course of Tryptophan (Trp) levels, Tryptophan catabolites (including kynurenines) and indoleamine-2,3-dioxygenase (IDO)-activity in post CA patients...
October 2016: Resuscitation
Abdulla A-B Badawy, Samina Bano
Rat liver tryptophan (Trp), kynurenine pathway metabolites, and enzymes deduced from product/substrate ratios were assessed following acute and/or chronic administration of kynurenic acid (KA), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), Trp, and the kynureni-nase inhibitors benserazide (BSZ) and carbidopa (CBD). KA activated Trp 2,3-dioxygenase (TDO), possibly by increasing liver 3-HAA, but inhibited kynurenine aminotransferase (KAT) and kynureninase activities with 3-HK as substrate. 3-HK inhibited kynureninase activity from 3-HK...
2016: International Journal of Tryptophan Research: IJTR
Abdulla A-B Badawy, Donald M Dougherty
Tryptophan (Trp) metabolism via the kynurenine pathway (KP) was assessed in normal healthy US volunteers at baseline and after acute Trp depletion (ATD) and acute Trp loading (ATL) using amino acid formulations. The hepatic KP accounts for ~90% of overall Trp degradation. Liver Trp 2,3-dioxygenase (TDO) contributes ~70% toward Trp oxidation, with the remainder achieved by subsequent rate-limiting enzymes in the KP. TDO is not influenced by a 1.15 g Trp load, but is maximally activated by a 5.15 g dose. We recommend a 30 mg/kg dose for future ATL studies...
2016: International Journal of Tryptophan Research: IJTR
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