Nilsson, L. K. et al. Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. Schizophr. Res. 80, 315-322

University of Gothenburg, Goeteborg, Västra Götaland, Sweden
Schizophrenia Research (Impact Factor: 3.92). 01/2006; 80(2-3):315-22. DOI: 10.1016/j.schres.2005.07.013
Source: PubMed


Previous studies have shown that endogenous brain levels of kynurenic acid (KYNA), a glutamate receptor antagonist, are elevated in patients with schizophrenia. Here we analyse KYNA in the cerebrospinal fluid (CSF) from a large cohort, including male healthy controls (n=49) and male patients with schizophrenia (n=90). We found that male patients with schizophrenia had significantly higher levels of CSF KYNA compared to healthy male controls (1.45 nM+/-0.10 vs. 1.06 nM+/-0.06 in the control group). Furthermore, when the patients with schizophrenia were divided into subgroups we found that CSF KYNA levels were significantly elevated in drug-naïve, first episode patients (1.53 nM+/-0.19, n=37) and in patients undergoing treatment with antipsychotic drugs (1.53 nM+/-0.17, n=34) compared to healthy male controls. No elevated CSF KYNA levels were detected in drug-free patients with schizophrenia, i.e. patients previously undergoing antipsychotic medications but drug-free at time of sampling (1.16 nM+/-0.10, n=19). Present results confirm that CSF KYNA concentration is elevated in patients with schizophrenia and are consistent with the hypothesis that KYNA contributes to the pathophysiology of the disease.

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Available from: Alina Aikaterini Karanti, Jun 18, 2014
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    • "For long KYNA has been implicated in schizophrenia and a central elevation of the compound is one of the most consistently found biochemical aberrations of the disease (Erhardt et al., 2001; Nilsson et al., 2005; Linderholm et al., 2012; Schwarcz et al., 2001; Sathysuikumar et al., 2011). In addition, cerebrospinal fluid (CSF) KYNA is also elevated in euthymic bipolar patients with a history of psychosis (Olsson et al., 2010, 2012). "
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    ABSTRACT: Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan, is elevated in the brain of patients with psychotic disorders. Therefore, lowering brain KYNA levels might be a novel approach in the treatment of psychotic disorders. The present in vivo electrophysiological study aimed to investigate the effect of an inhibitor of kynurenine aminotransferase (KAT) II, the primary enzyme for KYNA synthesis, on dopamine (DA) neurons in the ventral tegmental area (VTA). Acute administration of the KAT II inhibitor PF-04859989 (5 or 10 mg/kg) was associated with a short-onset, time-dependent decrease in firing rate and burst activity of DA neurons, both parameters reaching a 50% reduction within 45 min. Furthermore, PF-04859989 reduced the number of spontaneously active DA cells as measured 4- 6 after administration. Pretreatment with D-cycloserine (30 mg/kg) or CGP-52432 (10mg/kg) prevented the inhibitory action of PF-04859989 (5 mg/kg) on firing rate and burst firing activity. In contrast, pretreatment with methyllycaconitine (MLA, 4 mg/kg) did not change the response, whereas picrotoxin (4.5 mg/kg) partially prevented the inhibitory effects of PF-04859989 (5 mg/kg, i.v.). Our results show that a specific inhibition of KAT II is associated with a marked reduction in VTA DA firing activity. This effect appears to be specifically executed by NMDA-receptors and mediated indirectly via a GABA(B)-receptor-induced disinhibition of DA neurons. Our findings are in line with the view that endogenous KYNA, by modulation of the NMDA-receptor, exerts important physiological roles in the brain.
    Neuropharmacology 10/2015; 102. DOI:10.1016/j.neuropharm.2015.10.028 · 5.11 Impact Factor
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    • "Alterations in the KP pathway have been described in a number of psychiatric conditions, including schizophrenia (Erhardt et al., 2001; Nilsson et al., 2005), bipolar disorder (Olsson et al., 2012) and suicidality (Bay-Richter et al., 2015; Erhardt et al., 2013), but also in neurodegenerative conditions like Alzheimer's (AD), Parkinson's, Huntington's (HD) diseases and amyotrophic lateral sclerosis (ALS) (Schwarcz et al., 2012). Thus, in psychosis, KYNA and its precursor KYN are increased in cerebrospinal fluid (CSF) and post mortem brain tissue (Erhardt et al., 2001; Sathyasaikumar et al., 2011; Schwarcz et al., 2001). "
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    ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system, with a high rate of neurocognitive symptoms for which the molecular background is still uncertain. There is accumulating evidence for dysregulation of the kynurenine pathway (KP) in different psychiatric and neurodegenerative conditions. We here report the first comprehensive analysis of cerebrospinal fluid (CSF) kynurenine metabolites in MS patients of different disease stages and in relation to neurocognitive symptoms.
    Brain Behavior and Immunity 07/2015; DOI:10.1016/j.bbi.2015.07.016 · 5.89 Impact Factor
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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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