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

Maryland Psychiatric Research Center, Baltimore, MD, USA.
Schizophrenia Bulletin (Impact Factor: 8.45). 10/2010; 37(6):1147-56. DOI: 10.1093/schbul/sbq112
Source: PubMed


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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Available from: Robert P Mcmahon, Oct 05, 2015
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    • "The previous enzyme inhibition results should apply to situations in which there is a temporary reduction in enzyme activity caused either by reduced immune system induction or the presence of an external inhibitory compound originating in the environment or polypharmaceutical treatment. Genetic deletion should reproduce the situation in which there is a permanent loss of enzyme protein or enzyme activity (Sathyasaikumar et al., 2011) such as that occasioned by single nucleotide polymorphisms (Holtze et al., 2012; Wonodi et al., 2011, 2014). Both models may, therefore, have clinical relevance. "
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    ABSTRACT: Glutamate receptors sensitive to N-methyl-D-aspartate (NMDA) are involved in embryonic brain development but their activity may be modulated by the kynurenine pathway of tryptophan metabolism which includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Our previous work has shown that prenatal inhibition of the pathway produces abnormalities of brain development. In the present study kynurenine and probenecid (both 100mg/kg, doses known to increase kynurenic acid levels in the brain) were administered to female Wistar rats on embryonic days E14, E16 and E18 of gestation and the litter was allowed to develop to post-natal day P60. Western blotting revealed no changes in hippocampal expression of several proteins previously found to be altered by inhibition of the kynurenine pathway including the NMDA receptor subunits GluN1, GluN2A and GluN2B, as well as doublecortin, Proliferating Cell Nuclear Antigen (PCNA), sonic hedgehog and unco-ordinated (unc)-5H1 and 5H3. Mice lacking the enzyme kynurenine-3-monoxygenase (KMO) also showed no changes in hippocampal expression of several of these proteins or the 70kDa and 100kDa variants of Disrupted in Schizophrenia-1 (DISC1). Electrical excitability of pyramidal neurons in the CA1 region of hippocampal slices was unchanged, as was paired-pulse facilitation and inhibition. Long-term potentiation was decreased in the kynurenine-treated rats and in the KMO(-/-) mice, but galantamine reversed this effect in the presence of nicotinic receptor antagonists, consistent with evidence that it can potentiate glutamate at NMDA receptors. It is concluded that interference with the kynurenine pathway in utero can have lasting effects on brain function of the offspring, implying that the kynurenine pathway is involved in the regulation of early brain development.
    Neuroscience 09/2015; DOI:10.1016/j.neuroscience.2015.09.022 · 3.36 Impact Factor
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    • "A nonsynonymous single nucleotide polymorphism (SNP) in the KMO gene has been shown to affect the CSF KYNA levels in patients with schizophrenia39 and bipolar disorder.8 In addition, the activity7 and expression8 of the KMO enzyme was found to be reduced in prefrontal cortex in patients with schizophrenia and bipolar disorder patients with psychosis. Furthermore, a recent study suggests that the function of other enzymes in the pathway is worth investigating as well. "
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    ABSTRACT: Several studies suggest a role for kynurenic acid (KYNA) in the pathophysiology of schizophrenia. It has been proposed that increased brain KYNA levels in schizophrenia result from a pathological shift in the kynurenine pathway toward enhanced KYNA formation, away from the other branch of the pathway leading to quinolinic acid (QUIN). Here we investigate the levels of QUIN in cerebrospinal fluid (CSF) of patients with schizophrenia and healthy controls, and relate those to CSF levels of KYNA and other kynurenine metabolites from the same individuals. CSF QUIN levels from stable outpatients treated with olanzapine (n = 22) and those of controls (n = 26) were analyzed using liquid chromatography-mass spectrometry. No difference in CSF QUIN levels between patients and controls was observed (20.6 ± 1.5 nM vs. 18.2 ± 1.1 nM, P = 0.36). CSF QUIN was positively correlated to CSF kynurenine and CSF KYNA in patients but not in controls. The CSF QUIN/KYNA ratio was lower in patients than in controls (P = 0.027). In summary, the present study offers support for an over-activated and imbalanced kynurenine pathway, favoring the production of KYNA over QUIN in patients with schizophrenia.
    International Journal of Tryptophan Research 09/2014; 7:15-22. DOI:10.4137/IJTR.S16800
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    • "Although plasma quinolinic acid was not measured (Myint et al., 2011) the kynurenic acid/kynurenine ratio was lower in patients, suggesting that the appearance of psychotic symptoms coincides with decrease in the neuroprotective ratio and increased activity in the neurotoxic arm of the pathway. In contrast, brain levels of kynurenic acid was found to be increased in both post mortem brains and cerebrospinal fluid of patients with chronic schizophrenia (Sathyasaikumar et al., 2011; Schwarcz et al., 2001; Erhardt et al., 2001). An increase in brain kynurenic acid would block the NMDAR analogous to one of the most potent pharmacological triggers of psychosis, the phencyclidine (PCP)/ketamine induced psychosis, consistent with the NMDAR hypofunction theory of schizophrenia (Moghaddam et al., 1997; Muller and Schwarz, 2006). "
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    ABSTRACT: Infections during pregnancy and subsequent maternal immune activation (MIA) increase risk for schizophrenia in offspring. The progeny of rodents injected with the viral infection mimic polyI:C during gestation display brain and behavioural abnormalities but the underlying mechanisms are unknown. Since the blood kynurenine pathway (KP) of tryptophan degradation impacts brain function and is strongly regulated by the immune system, we tested if KP changes occur in polyI:C offspring at preadolescence. We also tested whether MK801-induced hyperlocomotion, a behaviour characteristic of adult polyI:C offspring, is prevented by adolescent treatment with celecoxib, a COX-2 inhibitor that impacts the KP. Pregnant rats were treated with polyIC (4mg/kg, i.v.) or vehicle on gestational day 19. Serum levels of KP metabolites were measured in offspring of polyI:C or vehicle treated dams at postnatal day (PND) 31-33 using HPLC/GCMS. Additional polyI:C or vehicle exposed offspring were given celecoxib or vehicle between PND35-46 and tested with MK801 (0.3mg/kg) in adulthood (PND>90). Prenatal polyI:C resulted in increases in the serum KP neurotoxic metabolite quinolinic acid at PND31-33 (105%, p=0.014). In contrast, the neuroprotective kynurenic acid and its precursor kynurenine were significantly decreased (28% p=0.027, and 31% p=0.033 respectively). Picolinic acid, another neuroprotective KP metabolite, was increased (31%, p=0.014). Adolescent treatment with celecoxib (2.5 and 5 mg/kg/day, i.p.) prevented the development of MK-801-induced hyperlocomotion in adult polyI:C offspring. Our study reveals the blood KP as a potential mechanism by which MIA interferes with postnatal brain maturation and associated behavioural disturbances and emphasises the preventative potential of inflammation targeting drugs.
    Brain Behavior and Immunity 05/2014; DOI:10.1016/j.bbi.2014.05.011 · 5.89 Impact Factor
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