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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Journal ArticleDOI
Kynurenine-3-monooxygenase (KMO) broadly inhibits viral infections via triggering NMDAR/Ca2+ influx and CaMKII/ IRF3-mediated IFN-β production
Jin Zhao,Jiaoshan Chen,Congcong Wang,Yajie Liu,Minchao Li,Yanjun Li,Ruiting Li,Zirong Han,Junjian Wang,Ling Chen,Yuelong Shu,Genhong Cheng,Caijun Sun +12 more
TL;DR: KMO and its enzymatic product QUIN were potential therapeutics against emerging pathogenic viruses and effectively inhibited viral infections and alleviated disease progression in mice.
Journal ArticleDOI
Development of a Rapid Fluorescence-Based High-Throughput Screening Assay to Identify Novel Kynurenine 3-Monooxygenase Inhibitor Scaffolds.
TL;DR: A facile fluorescence-based K MO assay optimized for high-throughput screening (HTS) that achieves a throughput approximately 20-fold higher than the fastest KMO assay currently reported.
Book ChapterDOI
Towards an Integrated View of Early Molecular Changes Underlying Vulnerability to Social Stress in Psychosis.
TL;DR: A model wherein inflammation and oxidative stress act as a first hit, producing altered parvalbumin interneuron development, NMDAR hypofunction, microglial priming, and sensitivity to a second hit of peripubertal social stress is proposed.
Journal Article
Old and new neuroendocrine molecules: somatostatin, cysteamine, pantethine and kynurenine
TL;DR: There have been highly important developments in neuroendocrinology since the early findings of Selye, and as new perspectives the KP may be involved in the modulation of neuroendrocrine processes: different agonists and antagonists of glutamate receptors regulate the hypothalamic-pituitary-adrenal axis and kynurenic acid augments the anxiolytic stress responses in neonatal chicks.
Journal ArticleDOI
Metabolismo do triptofano em transtornos mentais: um enfoque na esquizofrenia
Michelle S. Carvalho,Camila M. Yonamine,Caroline Dal Mas,Dayane Felix Silva Nunes,Mirian A. F. Hayashi +4 more
TL;DR: O triptofano (TRP) is an aminoacido essencial, encontrado no plasma principalmente ligado a albumina, e com apenas uma pequena fracao encontradada na forma livre as mentioned in this paper.
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