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
Reads0
Chats0
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
Meta-analysis of Cerebrospinal Fluid Cytokine and Tryptophan Catabolite Alterations in Psychiatric Patients: Comparisons Between Schizophrenia, Bipolar Disorder, and Depression
TL;DR: There is preliminary evidence for similarities in the pattern of CSF cytokine and tryptophan catabolite alterations across major psychiatric disorders, although findings must be interpreted with caution in light of small numbers of studies/subjects.
Journal ArticleDOI
Autoimmunity, inflammation, and psychosis: a search for peripheral markers.
TL;DR: Animal models of psychotic conditions (maternal stress and inflammation paradigms) suggest that such monocyte/microglia activation could be seen as the result of a combination of genetic predisposition and an immune-mediated two-hit model.
Journal ArticleDOI
Inflammatory processes in schizophrenia: A promising neuroimmunological target for the treatment of negative/cognitive symptoms and beyond
TL;DR: Given the limited efficacy of currently available antipsychotic drugs to ameliorate negative and cognitive symptoms, the further exploration of inflammatory mechanisms and anti-inflammatory strategies may open fruitful new avenues for improved treatment of symptoms undermining affective, emotional, social and cognitive functions pertinent to schizophrenic disease.
Journal ArticleDOI
Inflammation and the two-hit hypothesis of schizophrenia
TL;DR: This review analyzes the literature on inflammation and schizophrenia, with a particular focus on comorbidity, biomarkers, and environmental insults and identifies several mechanisms by which inflammation could influence the development of schizophrenia via the two-hit hypothesis.
Journal ArticleDOI
The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders
TL;DR: A biochemical pathway that remains under‐recognized in its implications for brain function is targeted, even though it can be responsible for moderating the activity of two neurotransmitters fundamentally involved in cognition – glutamate and acetylcholine.
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.