Impaired Kynurenine Pathway Metabolism in The Prefrontal Cortex of Individuals With Schizophrenia
Korrapati V. Sathyasaikumar,Erin K. Stachowski,Ikwunga Wonodi,Rosalinda C. Roberts,Rosalinda C. Roberts,Arash Rassoulpour,Robert P. McMahon,Robert Schwarcz +7 more
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TLDR
The present results further support the hypothesis that the normalization of cortical KP metabolism may constitute an effective new treatment strategy in SZ.Abstract:
The levels of kynurenic acid (KYNA), an astrocyte-derived metabolite of the branched kynurenine pathway (KP) of tryptophan degradation and antagonist of α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors, are elevated in the prefrontal cortex (PFC) of individuals with schizophrenia (SZ). Because endogenous KYNA modulates extracellular glutamate and acetylcholine levels in the PFC, these increases may be pathophysiologically significant. Using brain tissue from SZ patients and matched controls, we now measured the activity of several KP enzymes (kynurenine 3-monooxygenase [KMO], kynureninase, 3-hydroxyanthranilic acid dioxygenase [3-HAO], quinolinic acid phosphoribosyltransferase [QPRT], and kynurenine aminotransferase II [KAT II]) in the PFC, ie, Brodmann areas (BA) 9 and 10. Compared with controls, the activities of KMO (in BA 9 and 10) and 3-HAO (in BA 9) were significantly reduced in SZ, though there were no significant differences between patients and controls in kynureninase, QPRT, and KAT II. In the same samples, we also confirmed the increase in the tissue levels of KYNA in SZ. As examined in rats treated chronically with the antipsychotic drug risperidone, the observed biochemical changes were not secondary to medication. A persistent reduction in KMO activity may have a particular bearing on pathology because it may signify a shift of KP metabolism toward enhanced KYNA synthesis. The present results further support the hypothesis that the normalization of cortical KP metabolism may constitute an effective new treatment strategy in SZ.read more
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Maternal genotype determines kynurenic acid levels in the fetal brain: Implications for the pathophysiology of schizophrenia:
Sarah Beggiato,Francesca M. Notarangelo,Korrapati V. Sathyasaikumar,Flaviano Giorgini,Robert Schwarcz +4 more
TL;DR: The disproportionate kynurenic acid increase in the brain of Kmo+/− animals indicates that the maternal Kmo genotype may play a key role in the pathophysiology of schizophrenia.
Journal ArticleDOI
Maternal protein restriction during gestation and lactation in the rat results in increased brain levels of kynurenine and kynurenic acid in their adult offspring.
Paula Honório de Melo Martimiano,Paula Honório de Melo Martimiano,Andre Oliveira,Andre Oliveira,Véronique Ferchaud-Roucher,Mikaël Croyal,Audrey Aguesse,Isabelle Grit,Khadija Ouguerram,Sandra Lopes de Souza,Bertrand Kaeffer,Francisco Bolaños-Jiménez +11 more
TL;DR: Results show that early protein deficiency induces selective and long‐lasting changes in brain kynurenine metabolism, which might contribute to the risk of developing psychiatric disorders induced by early malnutrition.
Journal ArticleDOI
Effect of kynurenic acid on development and aging in wild type and vermilion mutants of Drosophila melanogaster.
TL;DR: Present data support the role of downstream Kyn metabolites in aging mechanisms and observation of the toxic effect of KYNA in Drosophila pupae was the first (to the best of the authors' knowledge) observation.
Journal ArticleDOI
Effects of neuroactive metabolites of the tryptophan pathway on working memory and cortical thickness in schizophrenia.
Junchao Huang,Jinghui Tong,Ping Zhang,Yanfang Zhou,Yimin Cui,Shuping Tan,Zhiren Wang,Fude Yang,Peter Kochunov,Joshua Chiappelli,Baopeng Tian,Li Tian,Yunlong Tan,L. Elliot Hong +13 more
TL;DR: In this paper, the effects of tryptophan metabolites such as kynurenic acid (KYNA), 5-hydroxyindole (5-HI), and quinolinic acid (QUIN) on cognitive performance in MATRICS Consensus Cognitive Battery and cortical thickness measured by magnetic resonance imaging were obtained.
Journal ArticleDOI
Prenatal Kynurenine Elevation Elicits Sex-Dependent Changes in Sleep and Arousal During Adulthood: Implications for Psychotic Disorders
Katherine M Rentschler,Annalisa M. Baratta,Audrey L Ditty,Nathan T J Wagner,Courtney J Wright,Snezana Milosavljevic,Jessica A. Mong,Ana Pocivavsek +7 more
TL;DR: In this paper, the effects of kynurenic acid (KYNA) exposure on sleep behavior in adult male and female offspring were examined using electroencephalogram and electromyogram telemetry and determined sex differences in sleep and arousal.
References
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Journal Article
Protein Measurement with the Folin Phenol Reagent
TL;DR: Procedures are described for measuring protein in solution or after precipitation with acids or other agents, and for the determination of as little as 0.2 gamma of protein.
Journal ArticleDOI
Common regions of the human frontal lobe recruited by diverse cognitive demands.
John S. Duncan,Adrian M. Owen +1 more
TL;DR: In this paper, the authors reviewed patterns of frontal-lobe activation associated with a broad range of different cognitive demands, including aspects of perception, response selection, executive control, working memory, episodic memory and problem solving.
Journal ArticleDOI
Glutamate and Schizophrenia: Beyond the Dopamine Hypothesis
TL;DR: Hypofunction of the NMDA receptor, possibly on critical GABAergic inter-neurons, may contribute to the pathophysiology of schizophrenia.
Journal ArticleDOI
The Brain Metabolite Kynurenic Acid Inhibits α7 Nicotinic Receptor Activity and Increases Non-α7 Nicotinic Receptor Expression: Physiopathological Implications
Corey Hilmas,Edna F. R. Pereira,Manickavasagom Alkondon,Arash Rassoulpour,Robert Schwarcz,Edson X. Albuquerque +5 more
TL;DR: It is demonstrated that nAChRs are targets for KYNA and suggest a functionally significant cross talk between the nicotinic cholinergic system and the kynurenine pathway in the brain.
Journal ArticleDOI
A glycine site associated with N-methyl-D-aspartic acid receptors: characterization and identification of a new class of antagonists.
TL;DR: Kynurenate‐type compounds inhibit glycine binding and are suggested to form a novel class of antagonists of the NMDA receptor acting through the glycine site, suggesting the existence of a dual and opposite modulation of NMDA receptors by endogenous ligands.