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Journal ArticleDOI

Impaired Kynurenine Pathway Metabolism in The Prefrontal Cortex of Individuals With Schizophrenia

TL;DR: 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.

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Citations
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Journal ArticleDOI
23 Nov 2020
TL;DR: The impact of sleep deprivation on tryptophan metabolism and associated complication in the brain is linked to increased production and accumulation of kynurenic acid in various regions of the brain.
Abstract: Sleep has a regulatory role in maintaining metabolic homeostasis and cellular functions. Inadequate sleep time and sleep disorders have become more prevalent in the modern lifestyle. Fragmentation of sleep pattern alters critical intracellular second messengers and neurotransmitters which have key functions in brain development and behavioral functions. Tryptophan metabolism has also been found to get altered in SD and it is linked to various neurodegenerative diseases. The kynurenine pathway is a major regulator of the immune response. Adequate sleep alleviates neuroinflammation and facilitates the cellular clearance of metabolic toxins produced within the brain, while sleep deprivation activates the enzymatic degradation of tryptophan via the kynurenine pathway, which results in an increased accumulation of neurotoxic metabolites. SD causes increased production and accumulation of kynurenic acid in various regions of the brain. Higher levels of kynurenic acid have been found to trigger apoptosis, leads to cognitive decline, and inhibit neurogenesis. This review aims to link the impact of sleep deprivation on tryptophan metabolism and associated complication in the brain.

28 citations

Journal ArticleDOI
TL;DR: Relationships between concentrations of cerebrospinal fluid (CSF) kynurenic acid (KYNA) and suicidal behavior were evaluated in 59 patients with psychosis after 22 years of follow-up.
Abstract: Relationships between concentrations of cerebrospinal fluid (CSF) kynurenic acid (KYNA) and suicidal behavior were evaluated in 59 patients with psychosis after 22 years of follow-up. Three patients died from suicide and nine patients had a history of attempted suicide. Patients with attempted suicide had significantly lower concentrations of CSF KYNA.

28 citations


Cites background from "Impaired Kynurenine Pathway Metabol..."

  • ...Elevated concentrations of KYNA have been found in the cerebrospinal fluid (CSF) (Nilsson et al., 2005) and in the postmortem prefrontal cortex (Sathyasaikumar et al., 2011) of patients with schizophrenia....

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  • ..., 2005) and in the postmortem prefrontal cortex (Sathyasaikumar et al., 2011) of patients with schizophrenia....

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Journal ArticleDOI
TL;DR: Animals given repeated injections of LPS showed a more robust induction of the kynurenine pathway in contrast to animals receiving a single injection, which may be valuable in light of data showing the importance of this pathway in psychiatric disorders.
Abstract: The immune system has been recognized as a potential contributor to psychiatric disorders. In animals, lipopolysaccharide (LPS) is used to induce inflammation and behaviors analogous to some of the symptoms in these disorders. Recent data indicate that the kynurenine pathway contributes to LPS-induced aberrant behaviors. However, data are inconclusive regarding optimal LPS dose and treatment strategy. Here, we therefore aimed to evaluate the effects of single versus repeated administration of LPS on the kynurenine pathway. Adult C57BL6 mice were given 0.83 mg/kg LPS as a single or a repeated injection (LPS + LPS) and sacrificed after 24, 48, 72, or 120 h. Mice receiving LPS + LPS had significantly elevated brain kynurenine levels at 24 and 48 h, and elevated serum kynurenine at 24, 48 and 72 h. Brain kynurenic acid and quinolinic acid were significantly increased at 24 and 48 h in mice receiving LPS + LPS, whereas serum kynurenic acid levels were significantly decreased at 24 h. The increase of brain kynurenic acid by LPS + LPS was likely unrelated to the higher total dose as a separate group of mice receiving 1.66 mg/kg LPS as single injection 24 h prior to sacrifice did not show increased brain kynurenic acid. Serum quinolinic acid levels were not affected by LPS + LPS compared to vehicle. Animals given repeated injections of LPS showed a more robust induction of the kynurenine pathway in contrast to animals receiving a single injection. These results may be valuable in light of data showing the importance of the kynurenine pathway in psychiatric disorders.

26 citations

Journal ArticleDOI
01 Nov 2017-Sleep
TL;DR: The results introduce kynurenine pathway metabolism and formation of KYNA as a novel molecular target contributing to sleep disruptions and cognitive impairments.
Abstract: Study objectives Tryptophan metabolism via the kynurenine pathway may represent a key molecular link between sleep loss and cognitive dysfunction. Modest increases in the kynurenine pathway metabolite kynurenic acid (KYNA), which acts as an antagonist at N-methyl-d-aspartate and α7 nicotinic acetylcholine receptors in the brain, result in cognitive impairments. As glutamatergic and cholinergic neurotransmissions are critically involved in modulation of sleep, our current experiments tested the hypothesis that elevated KYNA adversely impacts sleep quality. Methods Adult male Wistar rats were treated with vehicle (saline) and kynurenine (25, 50, 100, and 250 mg/kg), the direct bioprecursor of KYNA, intraperitoneally at zeitgeber time (ZT) 0 to rapidly increase brain KYNA. Levels of KYNA in the brainstem, cortex, and hippocampus were determined at ZT 0, ZT 2, and ZT 4, respectively. Analyses of vigilance state-related parameters categorized as wake, rapid eye movement (REM), and non-REM (NREM) as well as spectra power analysis during NREM and REM were assessed during the light phase. Separate animals were tested in the passive avoidance paradigm, testing contextual memory. Results When KYNA levels were elevated in the brain, total REM duration was reduced and total wake duration was increased. REM and wake architecture, assessed as number of vigilance state bouts and average duration of each bout, and theta power during REM were significantly impacted. Kynurenine challenge impaired performance in the hippocampal-dependent contextual memory task. Conclusions Our results introduce kynurenine pathway metabolism and formation of KYNA as a novel molecular target contributing to sleep disruptions and cognitive impairments.

25 citations

Book ChapterDOI
26 Nov 2014
TL;DR: Findings related to immune activation and inflammation in schizophrenia, major depression and Tourette's syndromes as examples for this concept are described and encouraging results from randomized clinical trials in schizophrenia and major depression show a benefit of anti-inflammatory therapy in these psychiatric disorders are discussed.
Abstract: Emil Kraepelin, the founder of modern psychiatric classification, and the Nobel laureate Julius Wagner von Jauregg highlighted the role of infections and the immune system in psychiatric disorders. It is well known that infections can trigger various psychiatric syndromes and influence the course of psychiatric disorders. Psychiatric symptoms during virulent infections, often presenting as encephalitis or meningitis, normally are diagnosed as mental disorders due to a general medical condition. On the other hand, an expanding research field underpins the view that infections and activation of the immune system may play a causative role in major psychiatric disorders such as schizophrenia or major depression. Also in other psychiatric syndromes, such as Tourette's syndrome, inflammation - partially based on infections - is involved. For this mild smoldering inflammatory process, the ‘mild (chronic) encephalitis' concept was developed. In this chapter, findings related to immune activation and inflammation in schizophrenia, major depression and Tourette's syndromes as examples for this concept are described. Moreover, encouraging results from randomized clinical trials in schizophrenia and major depression showing a benefit of anti-inflammatory therapy in these psychiatric disorders are discussed as examples for immunomodulating treatment approaches in psychiatric disorders. Further immunotherapies used in Tourette's syndrome or pediatric autoimmune disorders associated with streptococci are highlighted as further examples for such a therapeutic approach.

25 citations

References
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Journal Article
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.

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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.

2,429 citations


"Impaired Kynurenine Pathway Metabol..." refers result in this paper

  • ...The activity of 3-HAO, which catalyzes the formation of the NMDA receptor agonist quinolinic acid from 3hydroxyanthranilic acid, was found to be reduced in BA 9, ie, the dorsolateral subdivision of the PFC that is preferentially involved in sustaining attention and working memory.(48) A tendency toward lower 3-HAO activity was also observed in BA 10, though the results were not statistically significant....

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Journal ArticleDOI
TL;DR: Hypofunction of the NMDA receptor, possibly on critical GABAergic inter-neurons, may contribute to the pathophysiology of schizophrenia.
Abstract: 1. After 50 years of antipsychotic drug development focused on the dopamine D2 receptor, schizophrenia remains a chronic, disabling disorder for most affected individuals.

886 citations

Journal ArticleDOI
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.
Abstract: The tryptophan metabolite kynurenic acid (KYNA) has long been recognized as an NMDA receptor antagonist. Here, interactions between KYNA and the nicotinic system in the brain were investigated using the patch-clamp technique and HPLC. In the electrophysiological studies, agonists were delivered via a U-shaped tube, and KYNA was applied in admixture with agonists and via the background perfusion. Exposure (≥4 min) of cultured hippocampal neurons to KYNA (≥100 nm) inhibited activation of somatodendritic α7 nAChRs; the IC50 for KYNA was ∼7 μm. The inhibition of α7 nAChRs was noncompetitive with respect to the agonist and voltage independent. The slow onset of this effect could not be accounted for by an intracellular action because KYNA (1 mm) in the pipette solution had no effect on α7 nAChR activity. KYNA also blocked the activity of preterminal/presynaptic α7 nAChRs in hippocampal neurons in cultures and in slices. NMDA receptors were less sensitive than α7 nAChRs to KYNA. The IC50 values for KYNA-induced blockade of NMDA receptors in the absence and presence of glycine (10 μm) were ∼15 and 235 μm, respectively. Prolonged (3 d) exposure of cultured hippocampal neurons to KYNA increased their nicotinic sensitivity, apparently by enhancing α4β2 nAChR expression. Furthermore, as determined by HPLC with fluorescence detection, repeated systemic treatment of rats with nicotine caused a transient reduction followed by an increase in brain KYNA levels. These results demonstrate 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.

764 citations

Journal ArticleDOI
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.
Abstract: Membranes from rat telencephalon contain a single class of strychnine-insensitive glycine sites. That these sites are associated with N-methyl-D-aspartic acid (NMDA) receptors is indicated by the observations that [3H]glycine binding is selectively modulated by NMDA receptor ligands and, conversely, that several amino acids interacting with the glycine sites increase [3H]N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP) binding to the phencyclidine site of the NMDA receptor. The endogenous compound kynurenate and several related quinoline and quinoxaline derivatives inhibit glycine binding with affinities that are much higher than their affinities for glutamate binding sites. In contrast to glycine, kynurenate-type compounds inhibit [3H]TCP binding and thus are suggested to form a novel class of antagonists of the NMDA receptor acting through the glycine site. These results suggest the existence of a dual and opposite modulation of NMDA receptors by endogenous ligands.

623 citations


"Impaired Kynurenine Pathway Metabol..." refers background in this paper

  • ...linked to cognitive phenomena and psychosis, ie, the a7 nicotinic acetylcholine receptor (a7nAChR)(12) and the N-methyl-D-aspartate (NMDA) receptor.(13) By reducing...

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