CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-α: relationship to CNS immune responses and depression

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 IFN-alpha treatment 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 ~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 (sTNFR2) and monocyte chemoattractant protein (MCP)-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, QUIN, KA, and ultimately depressive symptoms.

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

“…For instance, the QA and the KA enzymatic pathways were reported to be equally activated in patients receiving IFN-a treatment, with QA and KA contributing approximately equally to symptom changes (Raison et al, 2010). Consistent with these data, a recent study reported an upregulation of KA in the saliva samples of HCs and schizophrenic subjects after a psychological stress challenge (Chiappelli et al, 2014).…”

A review of the relationship between proinflammatory cytokines and major depressive disorder

“…This scarcity is mainly due to the relative difficulty of obtaining CSF samples, higher costs and perceived level of discomfort. Nevertheless, current results are promising and show altered levels of proinflammatory biomarkers in CSF samples of depressed patients relative to healthy controls (Raison et al, 2010).…”

“…Quinolinic acid binds to N-methyl-D-aspartate receptors while also depleting tryptophan leading to a decrease in overall serotonin levels and an increase in glutamatergic activity commonly associated with depression (Sublette et al, 2011). This is believed to be the biochemical mechanism of neuronal damage and loss of neuronal plasticity that leads to an increase in suicide attempts among a subgroup of MDD patients with elevated plasma kynurenine levels (Sublette et al, 2011), although other studies have suggested that increased kynurenine levels without a decrease in tryptophan levels could also lead to depressive-like behavior in both animal models and human subjects (Raison et al, 2010). A number of animal studies also support the association of inflammatory states with depressive symptoms, decreased hippocampal volumes, and "sickness behavior" (Goshen et al, 2008;Goshen and Yirmiya, 2009;Lawson et al, 2013).…”

Depression in cancer: The many biobehavioral pathways driving tumor progression

“…In fact, increased levels of pro-inflammatory cytokines and reduced signaling of anti-inflammatory mediators, such as IL-10 and transforming growth factor beta (TGF-β), may direct the differentiation of T naïve cells towards the T helper 1 (Th1)/Th17 phenotype instead of T regulatory (T reg) cells, further promoting the production of pro-inflammatory mediators (e.g., IFN, IL-2) in a vicious circle 48,49 . Pro-inflammatory cytokines stimulate the activation of the enzyme indoleamine 2-3 dioxygenase (IDO), which converts tryptophan into kynurenine (KYN), leading to serotonin deprivation 50 . In microglial cells, KYN may be further converted into quinolinic acid (QUIN), a powerful N-methyl-D-aspartate (NMDA) agonist and stimulator of glutamate release.…”