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      Kynurenines in CNS disease: regulation by inflammatory cytokines

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          Abstract

          The kynurenine pathway (KP) metabolizes the essential amino acid tryptophan and generates a number of neuroactive metabolites collectively called the kynurenines. Segregated into at least two distinct branches, often termed the “neurotoxic” and “neuroprotective” arms of the KP, they are regulated by the two enzymes kynurenine 3-monooxygenase and kynurenine aminotransferase, respectively. Interestingly, several enzymes in the pathway are under tight control of inflammatory mediators. Recent years have seen a tremendous increase in our understanding of neuroinflammation in CNS disease. This review will focus on the regulation of the KP by inflammatory mediators as it pertains to neurodegenerative and psychiatric disorders.

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          IDO expression by dendritic cells: tolerance and tryptophan catabolism.

          Indoleamine 2,3-dioxygenase (IDO) is an enzyme that degrades the essential amino acid tryptophan. The concept that cells expressing IDO can suppress T-cell responses and promote tolerance is a relatively new paradigm in immunology. Considerable evidence now supports this hypothesis, including studies of mammalian pregnancy, tumour resistance, chronic infections and autoimmune diseases. In this review, we summarize key recent developments and propose a unifying model for the role of IDO in tolerance induction.
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            Cortical inhibitory neurons and schizophrenia.

            Impairments in certain cognitive functions, such as working memory, are core features of schizophrenia. Convergent findings indicate that a deficiency in signalling through the TrkB neurotrophin receptor leads to reduced GABA (gamma-aminobutyric acid) synthesis in the parvalbumin-containing subpopulation of inhibitory GABA neurons in the dorsolateral prefrontal cortex of individuals with schizophrenia. Despite both pre- and postsynaptic compensatory responses, the resulting alteration in perisomatic inhibition of pyramidal neurons contributes to a diminished capacity for the gamma-frequency synchronized neuronal activity that is required for working memory function. These findings reveal specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.
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              Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.

              Through the study of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), a previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and direct transcription. Recognition of the molecules involved in the IFN-alpha and IFN-gamma pathway has led to discoveries that a number of STAT family members exist and that other polypeptide ligands also use the Jak-STAT molecules in signal transduction.
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                Author and article information

                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                06 February 2014
                2014
                : 8
                : 12
                Affiliations
                Neuroinflammation Disease Biology Unit, Lundbeck Research USA Paramus, NJ, USA
                Author notes

                Edited by: Adam Denes, University of Manchester, UK

                Reviewed by: Robert Schwarcz, Maryland Psychiatric Research Center, USA; Robert Dantzer, MD Anderson Cancer Center, USA

                *Correspondence: Thomas Möller, Neuroinflammation Disease Biology Unit, Lundbeck Research USA, 215 College Rd., Paramus, NJ 07652, USA e-mail: tmoe@ 123456lundbeck.com

                This article was submitted to Neuroendocrine Science, a section of the journal Frontiers in Neuroscience.

                Article
                10.3389/fnins.2014.00012
                3915289
                24567701
                4bfe6031-c708-47fd-9e6d-20c4ef8881cc
                Copyright © 2014 Campbell, Charych, Lee and Möller.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 25 October 2013
                : 20 January 2014
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 237, Pages: 22, Words: 21275
                Categories
                Endocrinology
                Review Article

                Neurosciences
                ido,kmo,cns disease,kat,neuroinflammation,kynurenine,microglia,astrocytes
                Neurosciences
                ido, kmo, cns disease, kat, neuroinflammation, kynurenine, microglia, astrocytes

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