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Neuroactive kynurenines

Marta Flis, Kinga Szymona, Justyna Morylowska-Topolska, Anna Urbańska, Paweł Krukow, Martyna Kandefer-Szerszeń, Barbara Zdzisińska, Ewa M Urbańska, Hanna Karakuła-Juchnowicz
Kynurenic acid (KYNA) is a neuroactive metabolite of tryptophan formed in the brain and in the periphery, known to block ionotropic glutamate receptors and α7 nicotinic receptors, and to act as a ligand of G protein-coupled GPR35 receptors and human aryl hydrocarbon (AHR) receptors. KYNA seems to modulate a number of mechanisms involved in the pathogenesis of schizophrenia including dopaminergic transmission in mesolimbic and mesocortical areas or glutamatemediated neurotransmission. The kynurenine hypothesis of schizophrenia links the occurrence of positive and negative symptoms of schizophrenia and cognitive impairments characteristic for the disease with the disturbances of kynurenine pathway function...
September 29, 2016: Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego
J M Parrott, L Redus, D Santana-Coelho, J Morales, X Gao, J C O'Connor
The kynurenine pathway of tryptophan metabolism has an important role in mediating the behavioral effects of inflammation, which has implications in understanding neuropsychiatric comorbidity and for the development of novel therapies. Inhibition of the rate-limiting enzyme, indoleamine 2,3-dioxygenase (IDO), prevents the development of many of these inflammation-induced preclinical behaviors. However, dysregulation in the balance of downstream metabolism, where neuroactive kynurenines are generated, is hypothesized to be a functionally important pathogenic feature of inflammation-induced depression...
October 18, 2016: Translational Psychiatry
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
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
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
D J Allison, A R Josse, D A Gabriel, P Klentrou, D S Ditor
STUDY DESIGN: This study was a randomized, parallel-group, controlled clinical trial. OBJECTIVES: The purpose of this study was to examine the efficacy of targeting inflammation as a means of improving cognitive function in individuals with spinal cord injury. SETTING: Participants were recruited from the Niagara region of Ontario Canada and all testing occurred on-site at Brock University. METHODS: Indices of memory and verbal learning were assessed by means of the California Verbal Learning Test (CVLT)...
June 21, 2016: Spinal Cord
Alireza Nematollahi, Guanchen Sun, Gayan S Jayawickrama, W Bret Church
Kynurenine aminotransferase isozymes (KATs 1-4) are members of the pyridoxal-5'-phosphate (PLP)-dependent enzyme family, which catalyse the permanent conversion of l-kynurenine (l-KYN) to kynurenic acid (KYNA), a known neuroactive agent. As KATs are found in the mammalian brain and have key roles in the kynurenine pathway, involved in different categories of central nervous system (CNS) diseases, the KATs are prominent targets in the quest to treat neurodegenerative and cognitive impairment disorders. Recent studies suggest that inhibiting these enzymes would produce effects beneficial to patients with these conditions, as abnormally high levels of KYNA are observed...
2016: International Journal of Molecular Sciences
Lee Jong-Min, Vanessa Tan, David Lovejoy, Nady Braidy, Dominic B Rowe, Bruce J Brew, Gilles J Guillemin
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease characterized by a progressive degeneration of central and peripheral motor neurons, leading to the atrophy of voluntary muscles. It has been previously demonstrated that the kynurenine pathway (KP), the major biochemical pathway for tryptophan metabolism, is dysregulated in ALS. In particular, the neuroactive intermediate, quinolinic acid (QUIN) has been shown to accumulate with a concomitant decrease in other neuroprotective and immunomodulatory KP metabolites...
June 2, 2016: Neuropharmacology
Sophie Erhardt, Lilly Schwieler, Sophie Imbeault, Göran Engberg
The kynurenine pathway of tryptophan degradation generates several neuroactive compounds. Of those, kynurenic acid is an N-methyl-d-aspartate (NMDA) and alpha7 nicotinic receptor antagonist. The kynurenic acid hypothesis of schizophrenia is built upon the fact that kynurenic acid blocks glutamate receptors and is elevated in schizophrenia. Kynurenic acid tightly controls glutamatergic and dopaminergic neurotransmission and elevated brain levels appear related to psychotic symptoms and cognitive impairments...
May 28, 2016: Neuropharmacology
Stefano Comai, Antonella Bertazzo, Jeanne Vachon, Marc Daigle, Jean Toupin, Gilles Côté, Gustavo Turecki, Gabriella Gobbi
Aggressive behavior is one of the most challenging symptoms in psychiatry, and biological markers for aggression lack of large sample validations. Serotonin (5-HT) and other neuroactive compounds deriving from Tryptophan (Trp), including kynurenine (Kyn), have not yet been investigated in large cohorts of aggressive individuals to validate their potential as biomarkers of aggression. In 361 male inmates we measured serum levels of Trp, 5-hydroxytryptophan, 5-HT, Kyn, the ratios 5-HT/Trp∗1000 and Kyn/Trp∗1000, and performed Structured Clinical Interview for DSM-IV Axis-I and -II Disorders (SCID-I and -II), global assessment of functioning (GAF), and scales for aggressive behavior, impulsivity, adult attention-deficit/hyperactivity disorder (ADHD), and intelligent quotient (IQ)...
October 3, 2016: Progress in Neuro-psychopharmacology & Biological Psychiatry
Carlo Breda, Korrapati V Sathyasaikumar, Shama Sograte Idrissi, Francesca M Notarangelo, Jasper G Estranero, Gareth G L Moore, Edward W Green, Charalambos P Kyriacou, Robert Schwarcz, Flaviano Giorgini
Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway-kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites...
May 10, 2016: Proceedings of the National Academy of Sciences of the United States of America
Chai K Lim, Francisco J Fernández-Gomez, Nady Braidy, Cristina Estrada, Cristina Costa, Silvia Costa, Alban Bessede, Emiliano Fernandez-Villalba, Anna Zinger, Maria Trinidad Herrero, Gilles J Guillemin
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by loss of dopaminergic neurons and localized neuroinflammation occurring in the midbrain several years before the actual onset of symptoms. Neuroinflammation leads to microglia activation and release of a large number of proinflammatory mediators. The kynurenine pathway (KP) of tryptophan catabolism is one of the major regulators of the immune response and is also likely to be implicated in the inflammatory and neurotoxic events in Parkinsonism...
April 9, 2016: Progress in Neurobiology
Sarah M Clark, Ana Pocivavsek, James D Nicholson, Francesca M Notarangelo, Patricia Langenberg, Robert P McMahon, Joel E Kleinman, Thomas M Hyde, John Stiller, Teodor T Postolache, Robert Schwarcz, Leonardo H Tonelli
BACKGROUND: Neuroinflammatory processes are increasingly believed to participate in the pathophysiology of a number of major psychiatric diseases, including depression. Immune activation stimulates the conversion of the amino acid tryptophan to kynurenine, leading to the formation of neuroactive metabolites, such as quinolinic acid and kynurenic acid. These compounds affect glutamatergic neurotransmission, which plays a prominent role in depressive pathology. Increased tryptophan degradation along the kynurenine pathway (KP) has been proposed to contribute to disease etiology...
October 2016: Journal of Psychiatry & Neuroscience: JPN
Jennifer L Remus, Robert Dantzer
Inflammation and depression are closely inter-related; inflammation induces symptoms of depression and, conversely, depressed mood and stress favor an inflammatory phenotype. The mechanisms that mediate the ability of inflammation to induce symptoms of depression are intensively studied at the preclinical level. This review discusses how it has been possible to build animal models of inflammation-induced depression based on clinical data and to explore critical mechanisms downstream of inflammation. Namely, we focus on the ability of inflammation to increase the activity of the tryptophan-degrading enzyme, indoleamine 2,3 dioxygenase, which leads to the production of kynurenine and downstream neuroactive metabolites...
September 2016: International Journal of Neuropsychopharmacology
M Majewski, A Kozlowska, M Thoene, E Lepiarczyk, W J Grzegorzewski
The kynurenine pathway (KP) of L-tryptophan metabolism produces several neuroactive metabolites with an amino acid structure. These metabolites may play an important role in the pathophysiology of irritable bowel syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, AIDS-dementia complex, depression, epilepsy and the aging process. Modulation of the KP through inhibition or stimulation of enzyme synthesis and activity can be an alternative approach to traditional therapy. Furthermore, it may be responsible for the altered functioning of the enteric nervous system and the central nervous system...
February 2016: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
Martina Curto, Luana Lionetto, Andrea Negro, Matilde Capi, Francesca Perugino, Francesco Fazio, Maria Adele Giamberardino, Maurizio Simmaco, Ferdinando Nicoletti, Paolo Martelletti
BACKGROUND: The reported efficacy of memantine in the treatment of patients with cluster headache (CH) suggests that NMDA receptors are involved in mechanisms of nociceptive sensitization within the trigeminal system associated with CH. NMDA receptors are activated or inhibited by neuroactive compounds generated by tryptophan metabolism through the kynurenine pathway. In the accompanying manuscript, we have found that serum levels of all kynurenine metabolites are altered in patients with chronic migraine...
2015: Journal of Headache and Pain
Francesca M Notarangelo, Ana Pocivavsek
The kynurenine pathway (KP) of tryptophan degradation contains several neuroactive metabolites that may influence brain function in health and disease. Mounting focus has been dedicated to investigating the role of these metabolites during neurodevelopment and elucidating their involvement in the pathophysiology of psychiatric disorders with a developmental component, such as schizophrenia. In this review, we describe the changes in KP metabolism in the brain from gestation until adulthood and illustrate how environmental and genetic factors affect the KP during development...
March 1, 2016: Neuropharmacology
Haihua Lu, Jing Yu, Jun Wang, Linlin Wu, Hang Xiao, Rong Gao
Neuroactive metabolites in dopamine, serotonin and kynurenine metabolic pathways play key roles in several physiological processes and their imbalances have been implicated in the pathophysiology of a wide range of disorders. The association of these metabolites' alterations with various pathologies has raised interest in analytical methods for accurate quantification in biological fluids. However, simultaneous measurement of various neuroactive metabolites represents great challenges due to their trace level, high polarity and instability...
April 15, 2016: Journal of Pharmaceutical and Biomedical Analysis
Elena Y Bryleva, Lena Brundin
Suicide is a major global problem, claiming more than 800,000 lives annually. The neurobiological changes that underlie suicidal ideation and behavior are not fully understood. Suicidal patients have been shown to display elevated levels of inflammation both in the central nervous system and the peripheral blood. A growing body of evidence suggests that inflammation is associated with a dysregulation of the kynurenine pathway in suicidal patients, resulting in an imbalance of neuroactive metabolites. Specifically, an increase in the levels of the NMDA receptor agonist quinolinic acid and a simultaneous decrease in neuroprotective metabolites have been observed in suicidal patients, and may contribute to the development of suicidality via changes in glutamate neurotransmission and neuroinflammation...
January 26, 2016: Neuropharmacology
Guanchen Sun, Alireza Nematollahi, Naveed A Nadvi, Ann H Kwan, Cy M Jeffries, W Bret Church
Kynurenine aminotransferase (KAT) is a pyridoxal-5'-phosphate (PLP) dependent enzyme that catalyses kynurenine (KYN) to kynurenic acid (KYNA), a neuroactive product in the tryptophan metabolic pathway. Evidence suggests that abnormal levels of KYNA are involved in many neurodegenerative diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease and schizophrenia. Reducing KYNA production through inhibiting kynurenine aminotransferase 2 (KAT2) would be a promising approach to understanding and treating the related neurological and mental disorders...
May 2016: Protein Expression and Purification
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