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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Targeting of NMDA receptors in new treatments for schizophrenia
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TL;DR: This area merits more research evaluation, especially controlling for potential confounding factors such as clinical status, age, genetic background, psychotropic medications, BMI, and smoking.
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Targeted Deletion of Kynurenine 3-Monooxygenase in Mice: A NEW TOOL FOR STUDYING KYNURENINE PATHWAY METABOLISM IN PERIPHERY AND BRAIN
Flaviano Giorgini,Shao-Yi Huang,Korrapati V. Sathyasaikumar,Francesca M. Notarangelo,Marian A. R. Thomas,Margarita A. Tararina,Hui-Qiu Wu,Robert Schwarcz,Paul J. Muchowski,Paul J. Muchowski +9 more
TL;DR: Results provide further evidence that KMO plays a key regulatory role in the KP and indicate that Kmo−/− mice will be useful for studying tissue-specific functions of individual KP metabolites in health and disease.
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Kynurenines with neuroactive and redox properties: relevance to aging and brain diseases.
Jazmin Reyes Ocampo,Rafael Lugo Huitrón,Dinora F. González-Esquivel,Perla Ugalde-Muñiz,Anabel Jiménez-Anguiano,Benjamín Pineda,José Pedraza-Chaverri,Camilo Ríos,Verónica Pérez de la Cruz +8 more
TL;DR: Each kynurenine is described remarking their redox properties, their effects in experimental models, their alterations in the aging process, and their roles in bioenergetic and biosynthetic metabolism.
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Contributions of the d-serine pathway to schizophrenia
TL;DR: This review will focus on D-serine, a co-agonist at the NMDA receptor that in combination with glutamate, is required for full activation of this ion channel receptor.
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