CSF Concentrations of Brain Tryptophan and Kynurenines during Immune Stimulation with IFN-alpha: Relationship to CNS Immune Responses and Depression

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.
Molecular Psychiatry (Impact Factor: 14.5). 11/2009; 15(4):393-403. DOI: 10.1038/mp.2009.116
Source: PubMed


Cytokine-induced activation of indoleamine 2,3-dioxygenase (IDO) catabolizes L-tryptophan (TRP) into L-kynurenine (KYN), which is metabolized to quinolinic acid (QUIN) and kynurenic acid (KA). QUIN and KA are neuroactive and may contribute to the behavioral changes experienced by some patients during exposure to inflammatory stimuli such as interferon (IFN)-alpha. A relationship between depressive symptoms and peripheral blood TRP, KYN and KA during treatment with IFN-alpha has been described. However, whether peripheral blood changes in these IDO catabolites are manifest in the brain and whether they are related to central nervous system cytokine responses and/or behavior is unknown. Accordingly, TRP, KYN, QUIN and KA were measured in cerebrospinal fluid (CSF) and blood along with CSF concentrations of relevant cytokines, chemokines and soluble cytokine receptors in 27 patients with hepatitis C after approximately 12 weeks of either treatment with IFN-alpha (n=16) or no treatment (n=11). Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale. IFN-alpha significantly increased peripheral blood KYN, which was accompanied by marked increases in CSF KYN. Increased CSF KYN was in turn associated with significant increases in CSF QUIN and KA. Despite significant decreases in peripheral blood TRP, IFN-alpha had no effect on CSF TRP concentrations. Increases in CSF KYN and QUIN were correlated with increased CSF IFN-alpha, soluble tumor necrosis factor-alpha receptor 2 and monocyte chemoattractant protein-1 as well as increased depressive symptoms. In conclusion, peripheral administration of IFN-alpha activated IDO in concert with central cytokine responses, resulting in increased brain KYN and QUIN, which correlated with depressive symptoms.

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Available from: Charles L Raison, Jan 16, 2014
    • "This strong reduction of the protective KynA has been described as an important etiological mechanism (Myint et al., 2007aMyint et al., , , 2007b Ogawa et al., 2014). In addition, higher 3HK levels have been found in patients with schizophrenia (Myint et al., 2007aMyint et al., , , 2007bMyint et al., , , 2011) and similar findings have been observed in IFNα induced depression (Maes et al., 2001; Raison et al., 2010; Wichers et al., 2005). Together, our negative findings in this downstream pathway suggest that the underlying neurobiological mechanisms are distinct in postpartum psychiatric disorders compared to non-postpartum psychiatric disorders. "
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    ABSTRACT: Objectives: Women are at very high risk for the first onset of acute and severe mood disorders the first weeks after delivery. Tryptophan breakdown is increased as a physiological phenomenon of the postpartum period and might lead to vulnerability for affective psychosis (PP) and severe depression (PD). The aim of the current study was to investigate alterations in tryptophan breakdown in the physiological postpartum period compared to patients with severe postpartum mood disorders. Methods: We included 52 patients (29 with PP, 23 with PD), 52 matched healthy postpartum women and 29 healthy non-postpartum women. Analyzes of serum tryptophan metabolites were performed using LC-MS/MS system for tryptophan, kynurenine, 3-hydroxykynurenine, kynurenic acid and 5-hydroxyindoleacetic acid. Results: The first two months of the physiological postpartum period were characterized by low tryptophan levels, increased breakdown towards kynurenine and a downstream shift toward the 3-OH-kynurenine arm, away from the kynurenic acid arm. Kynurenine was significantly lower in patients with PP and PD as compared to healthy postpartum women (p=0.011 and p=0.001); the remaining tryptophan metabolites demonstrated few differences between patients and healthy postpartum women. Limitation: Low prevalence of the investigated disorders and strict exclusion criteria to obtain homogenous groups, resulted in relatively small sample sizes. Conclusion: The high kynurenine levels and increased tryptophan breakdown as a phenomenon of the physiological postpartum period was not present in patients with severe postpartum mood disorders. No differences were observed in the levels of the 'neurotoxic' 3-OH-kynurenine and the 'neuroprotective' kynurenic acid arms between patients and healthy postpartum women.
    No preview · Article · Oct 2015 · Journal of Affective Disorders
    • "pre) test was performed the following night. Animals were euthanized and tissue samples collected on day 8. [2] [4] [27]. In addition, the kynurenine/tryptophan ratio, an index of indoleamine 2,3-dioxygenase (IDO) activity, is increased in patients receiving IFN-therapy [2,4,5,35,]. "
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    ABSTRACT: Immunotherapy with the cytokine interferon-alpha (IFN-α) can induce symptoms of depression, and it is likely that the tryptophan-kynurenine pathway may be involved in this regard. In this study we investigated the effects of IFN-α on depression-like behaviour and central metabolites of the tryptophan-kynurenine pathway in rats. Secondly, we explored the modulating effects of an antidepressant (imipramine) and anti-inflammatory drug (celecoxib) on IFN-α-induced behavioural and pathophysiological changes in the brain. The following treatment groups were used: Control (saline), IFN-α (6×10(4) IU/kg s.c.), IFN-α + imipramine or IFN-α + celecoxib. Drugs were administered daily for 1 week. IFN-α treatment induced depression-like behaviour by increasing immobility in the forced swim test (FST), and decreased tryptophan levels in the brain. There was a trend for an increased kynurenine/tryptophan ratio, indicative of indoleamine 2,3-dioxygenase (IDO) activation, and increased quinolinic acid in the hippocampus. Imipramine decreased immobility in the FST, but did not reverse the IFN-α-induced changes in the tryptophan-kynurenine pathway. There was a trend for celecoxib to decrease immobility and to reverse the IFN-α-induced increase in the kynurenine/tryptophan ratio. Thus, our study provides further evidence for IFN-α-induced depression-like behaviour through central changes of the tryptophan-kynurenine pathway. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jul 2015 · Behavioural brain research
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    • "So far, alterations in CSF KYNA levels in MS have been reported for two smaller groups of MS patients, with lower levels compared to controls in the first study (Rejdak et al., 2002), and higher levels in patients experiencing clinical exacerbation (Raison et al., 2010; Rejdak et al., 2007). The KP has also been studied in blood of MS patients (Amirkhani et al., 2005) but the relevance of changes occurring in the periphery regarding intrathecal effects is uncertain since the correlation between KP blood and CSF levels is limited and varies depending on the KP metabolite measured (Raison et al., 2010). The aims of this study were to (i) investigate if different MS courses are reflected in changes of KP metabolites and (ii) to examine the relationship between kynurenines and neurocognitive symptoms in MS patients. "
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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.
    Full-text · Article · Jul 2015 · Brain Behavior and Immunity
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