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.

Download full-text


Available from: Charles L Raison, Jan 16, 2014
    • "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,]. "
    [Show abstract] [Hide abstract]
    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.
    Behavioural brain research 07/2015; 293. DOI:10.1016/j.bbr.2015.07.015 · 3.03 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "In some studies in patients with hepatitis or cancer who were treated with pro-inflammatory IFN-a therapy, increases in depression or depressive symptoms and increases of TRP degradation were found. This supported the hypothesis that increased IDO-mediated TRP metabolism along the KYN pathway could lead to the development of depressive symptoms (Capuron et al., 2003; Comai et al., 2011; Maes et al., 2001; Raison et al., 2010; Wichers et al., 2005). But in other studies no relationship could be detected between increase of tryptophan degradation and depressive symptoms, potentially due to the fact that most patients only developed mild depressive symptoms (Bannink et al., 2007; Van Gool et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Several studies have suggested that induced tryptophan (TRP) degradation through the kynurenine (KYN) pathway by the enzyme indoleamine 2,3-dioxygenase (IDO) is implicated in the relation between depression and inflammation. We investigated the role of tryptophan degradation in the relationship between inflammatory markers and depressive symptoms in the Netherlands Study of Depression and Anxiety (NESDA) and hypothesized that tryptophan degradation would mediate (part of) this association. Methods 2812 participants of NESDA were included in this study including 1042 persons with current major depressive disorder (MDD). Assessments of C-reactive protein (CRP), interleukin (IL)-6, tumor-necrosis factor (TNF)-α, KYN and TRP were obtained from fasting blood samples at the baseline assessment. Tryptophan degradation was estimated by calculating the ratio [KYN/TRP]. Depressive symptoms were measured with the Inventory of Depressive Symptomatology. Results Significant associations between inflammation and depressive symptoms were found for CRP and IL-6, for the total group and the subgroup of patients with current MDD. Adjustment for KYN/TRP did not attenuate these associations. There were no significant indirect effects for CRP on depressive symptoms mediated by KYN/TRP for the whole group (B = -0.032; 95% CI: -0.103-0.028) and for the subgroup of patients with current MDD (B = 0.059; 95% CI: -0.037-0.165). Also IL-6 did not indirectly affect depressive symptoms through KYN/TRP in the total group (B= -0.023; 95% CI: -0.093-0.045) and in the MDD subgroup B= 0.052; 95% CI: -0.019-0.144). Finally, no significant relation between depressive symptoms and KYN/TRP was found in the whole group (β=-0.019, p = 0.311) nor in the subgroup with MDD (β=0.025, p = 0.424). Conclusions We did not find indications for tryptophan degradation, measured by KYN/TRP, to mediate the relationship between inflammation and depressive symptoms.
    Psychoneuroendocrinology 07/2014; 45. DOI:10.1016/j.psyneuen.2014.03.013 · 4.94 Impact Factor
Show more