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

By Charles L Raison, Robert Dantzer, Keith W. Kelley, M. Lawson, B. Woolwine, G. Vogt, J. Spivey, Kuniaki Saito, Andrew H. Miller. Molecular Psychiatry, 2009

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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)-α. A relationship between depressive symptoms and peripheral blood TRP, KYN and KA during treatment with IFN-α 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-α (n=16) or no treatment (n=11). Depressive symptoms were assessed using the Montgomery–Asberg Depression Rating Scale. IFN-α 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-α had no effect on CSF TRP concentrations. Increases in CSF KYN and QUIN were correlated with increased CSF IFN-α, soluble tumor necrosis factor-α receptor 2 and monocyte chemoattractant protein-1 as well as increased depressive symptoms. In conclusion, peripheral administration of IFN-α activated IDO in concert with central cytokine responses, resulting in increased brain KYN and QUIN, which correlated with depressive symptoms.

Subfields: Behavioral Neuroscience, Biological Psychiatry, Experimental and Cognitive Psychology

View Paper: https://www.semanticscholar.org/paper/a1f6145408d22906e7b0a86f97ab06a846df65c3

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Citations in the corpus

The Link between Depression and Chronic Pain: Neural Mechanisms in the Brain (2017, background): “Furthermore, a high ratio of plasma kynurenine and tryptophan in patients undergoing IFN-α therapy has been shown to predict depression severity [42, 46, 47].”
From Stress to Inflammation and Major Depressive Disorder: A Social Signal Transduction Theory of Depression (2014, background): “Finally, cytokines have been found to reduce levels of serotonin and possibly other related neurotransmitters by decreasing the availability of its serotonin precursor, an essential amino acid called tryptophan (Konsman, Parnet, & Dantzer, 2002; Mattson, Maudsley, & Martin, 2004; Raison et al., 2010”
Psychoneuroimmunology Meets Neuropsychopharmacology: Translational Implications of the Impact of Inflammation on Behavior (2012, background): “In addition, studies have shown that increases in plasma kynurenine are manifested as increased kynurenine in the CSF of IFN-a-treated patients (Raison et al, 2010a, b, c).”
Depression as a microglial disease. (2015, positive): “The involvement of the microglial KP in mediating inflammation and stress-induced depression is supported by clinical studies demonstrating that IFN-/ immunotherapy increases tryptophan metabolism through the KP pathway, both in the periphery and in the CSF, and this increase is significantly correl”
Neuroinflammation and depression: A review (2020, background): “In addition, the KYN/TRY ratio (an indicator of the activation of the first step of the KYN pathway) was found to be increased in the plasma and CSF of patients having received IFN-α and to correlate with the intensity of depressive symptoms (Raison et al., 2010).”
Cytokine Targets in the Brain: Impact on Neurotransmitters and Neurocircuits (2013, background): “Inhibition of NOS has been shown to both increase BH4 and dopamine concentrations in the brain of rats treated with IFN-α.”
The Bidirectional Relationship of Depression and Inflammation: Double Trouble (2020, background): “IFN-α-induced depression development and severity in hepatitic C patients is directly associated with an increase in CSF and peripheral tryptophan metabolism through the kynurenine pathway (Capuron et al., 2002, 2003; Raison et al., 2010).”