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

ABSTRACT 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
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    • "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.
    Behavioural brain research 07/2015; 293. DOI:10.1016/j.bbr.2015.07.015 · 3.03 Impact Factor
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    • "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). "
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    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
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    • "Unfortunately the therapeutic effects of IFN-α are associated with CNS side effects in humans, and in particular with the manifestation of depression symptoms. Quinolinic acid and kynurenic acid may contribute to the behavioral changes experienced by patients during exposure to inflammatory stimuli such as IFN-α and relationship between depressive symptoms and peripheral blood tryptophan, kynurenate and kynurenic acid during treatment with IFN-α has been indeed described [1]. After recognition of the effects of IFN-α in CNS, several animal models of IFN-α-induced depression-like behaviour, also called sickness behaviour, have been developed in rodents using various preparations , dosing schedules or routes of administrations [2]. "
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    ABSTRACT: Therapeutic effects of Interferon-α (IFN-α are known to be associated with CNS toxicity in humans, and in particular with depression symptoms. Animal models of IFN-α-induced depression (sickness behaviour) have been developed in rodents using various preparations, dosing schedules or routes of administrations. In this work, Manganese Enhanced MRI (MEMRI) has been applied to investigate an experimental model of sickness behaviour induced by administration of IFN-α in rats. IFN-α (3.105 units/kg), or vehicle, was daily administered i.p., for 7 days in rats (n=20 IFN-α treated and n=20 controls). After treatment, animals were assigned to behavioural (n=10 treated, n=10 control) or MRI (n=10 treated and n=10 control) studies. Animals assigned to the MRI study received two repeated i.p. injections of MnCl2, before image acquisition. Images were acquired at 4.7T using T1 mapping for determination of Mn concentration in brain. After co-registration of T1 maps to a digital brain atlas, differences between brains of treated and untreated animals were assessed pixel-to-pixel by statistical analysis. Behavioural tests showed alterations in freezing and struggling parameters, as expected in an experimental model of sickness behaviour. MRI showed a well defined brain region, mainly contained in the visual cortex, in which Mn uptake was significantly lower in treated than in control animals, indicating probably altered functionality. No significant difference was detected in other brain regions. In addition, a statistically significant decrease in the volume of the pituitary gland, paralleled by a slight increase in its Mn content, was detected in treated animals. MEMRI provides both morphological and functional information in the brain of small laboratory animals and can constitute a valuable tool in the investigation of experimental models of psychiatric diseases.
    Magnetic Resonance Imaging 06/2014; 32(5). DOI:10.1016/j.mri.2014.02.006 · 2.09 Impact Factor
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