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
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
Citations
More filters
Journal ArticleDOI
Blood-based kynurenine pathway alterations in schizophrenia spectrum disorders: A meta-analysis.
TL;DR: A partial downregulation of the kynurenine pathway is observed in SSD patients, in particular during acute symptomatic states and in older age, effects that were independent from each other.
Journal ArticleDOI
Kynurenines, Gender and Neuroinflammation; Showcase Schizophrenia.
TL;DR: This review discusses the currently available literature on sex hormones and their effect on the kynurenine pathway in the context of the glutamatergic, dopaminergic and immunological features of schizophrenia.
Journal ArticleDOI
Central Nervous System Infection with Borna Disease Virus Causes Kynurenine Pathway Dysregulation and Neurotoxic Quinolinic Acid Production
Simone Formisano,Mady Hornig,Kavitha Yaddanapudi,Mansi Vasishtha,Loren H. Parsons,Thomas Briese,W. Ian Lipkin,Brent L. Williams +7 more
TL;DR: It is shown that BDV infection induces expression of key enzymes of the kynurenine pathway in brains of newborn and adult infected rats and cultured astroglioma cells, shunting tryptophan degradation toward the production of neurotoxic quinolinic acid.
Journal ArticleDOI
Peripheral Cortisol and Inflammatory Response to a Psychosocial Stressor in People with Schizophrenia
Matthew Glassman,Heidi J. Wehring,Ana Pocivavsek,Kelli M. Sullivan,Laura M. Rowland,Robert P. McMahon,Joshua Chiappelli,Fang Liu,Deanna L. Kelly +8 more
TL;DR: People with schizophrenia showed a decrease in cortisol from baseline following the Trier Social Stress Test as compared to an elevation from baseline seen in healthy controls, supporting HPA axis dysfunction in schizophrenia.
Journal ArticleDOI
Kynurenic acid and psychotic symptoms and personality traits in twins with psychiatric morbidity.
Magdalena E. Kegel,Viktoria Johansson,Lennart Wetterberg,Maria Bhat,Lilly Schwieler,Tyrone D. Cannon,Ina Schuppe-Koistinen,Ina Schuppe-Koistinen,Göran Engberg,Mikael Landén,Mikael Landén,Christina M. Hultman,Sophie Erhardt +12 more
TL;DR: The association between KYNA and psychotic symptoms further supports a role of KYNA in psychotic disorders and indicates genetic influences on CSF KYNA, TRP, IL-8 and TNF-α.
References
More filters
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.