Kynurenines in the mammalian brain: when physiology meets pathology (original) (raw)
Liebig, J. Über Kynurensäure. Justus Liebigs Ann. Chem.86, 125–126 (1853). Article Google Scholar
Leklem, J. E. Quantitative aspects of tryptophan metabolism in humans and other species: a review. Am. J. Clin. Nutr.24, 659–672 (1971). ArticleCASPubMed Google Scholar
Perkins, M. N. & Stone, T. W. An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res.247, 184–187 (1982). This paper introduces the opposing effects of QUIN and KYNA as agonist and antagonist, respectively, of glutamate receptors. ArticleCASPubMed Google Scholar
Parsons, C. G. et al. Novel systemically active antagonists of the glycine site of the _N_-methyl-D-aspartate receptor: electrophysiological, biochemical and behavioral characterization. J. Pharmacol. Exp. Ther.283, 1264–1275 (1997). CASPubMed Google Scholar
Maj, J., Rogoz, Z., Skuza, G. & Kolodziejczyk, K. Some central effects of kynurenic acid, 7-chlorokynurenic acid and 5,7- dichloro-kynurenic acid, glycine site antagonists. Pol. J. Pharmacol.46, 115–124 (1994). CASPubMed Google Scholar
Birch, P. J., Grossman, C. J. & Hayes, A. G. Kynurenic acid antagonises responses to NMDA via an action at the strychnine-insensitive glycine receptor. Eur. J. Pharmacol.154, 85–87 (1988). ArticleCASPubMed Google Scholar
Russi, P. et al. Nicotinylalanine increases the formation of kynurenic acid in the brain and antagonizes convulsions. J. Neurochem.59, 2076–2080 (1992). ArticleCASPubMed Google Scholar
Hilmas, C. et al. The brain metabolite kynurenic acid inhibits α7 nicotinic receptor activity and increases non-α7 nicotinic receptor expression: physiopathological implications. J. Neurosci.21, 7463–7473 (2001). In this paper, the authors identify the α7nAChR as a new and preferential target of KYNA. ArticleCASPubMedPubMed Central Google Scholar
Grilli, M. et al. Modulation of the function of presynaptic α7 and non-α7 nicotinic receptors by the tryptophan metabolites, 5-hydroxyindole and kynurenate in mouse brain. Br. J. Pharmacol.149, 724–732 (2006). ArticleCASPubMedPubMed Central Google Scholar
Wu, H. Q. et al. The astrocyte-derived α7 nicotinic receptor antagonist kynurenic acid controls extracellular glutamate levels in the prefrontal cortex. J. Mol. Neurosci.40, 204–210 (2010). ArticleCASPubMed Google Scholar
Stone, T. W. Kynurenic acid blocks nicotinic synaptic transmission to hippocampal interneurons in young rats. Eur. J. Neurosci.25, 2656–2665 (2007). ArticlePubMed Google Scholar
Wang, J. et al. Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J. Biol. Chem.281, 22021–22028 (2006). ArticleCASPubMed Google Scholar
DiNatale, B. C. et al. Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling. Toxicol. Sci.115, 89–97 (2010). ArticleCASPubMedPubMed Central Google Scholar
Moroni, F., Cozzi, A., Sili, M. & Mannaioni, G. Kynurenic acid: a metabolite with multiple actions and multiple targets in brain and periphery. J. Neural Transm.119, 133–139 (2012). ArticleCASPubMed Google Scholar
Mok, M. H., Fricker, A. C., Weil, A. & Kew, J. N. Electrophysiological characterisation of the actions of kynurenic acid at ligand-gated ion channels. Neuropharmacology57, 242–249 (2009). ArticleCASPubMed Google Scholar
Lopes, C. et al. Competitive antagonism between the nicotinic allosteric potentiating ligand galantamine and kynurenic acid at α7* nicotinic receptors. J. Pharmacol. Exp. Ther.322, 48–58 (2007). ArticleCASPubMed Google Scholar
Hardeland, R. et al. Indole-3-pyruvic and -propionic acids, kynurenic acid, and related metabolites as luminophores and free-radical scavengers. Adv. Exp. Med. Biol.467, 389–395 (1999). ArticleCASPubMed Google Scholar
Lugo-Huitron, R. et al. On the antioxidant properties of kynurenic acid: free radical scavenging activity and inhibition of oxidative stress. Neurotoxicol. Teratol.33, 538–547 (2011). ArticleCASPubMed Google Scholar
Stone, T. W. Neuropharmacology of quinolinic and kynurenic acids. Pharmacol. Rev.45, 310–379 (1993). Google Scholar
Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature478, 197–203 (2011). ArticleCASPubMed Google Scholar
Copeland, C. S., Neale, S. A. & Salt, T. E. Actions of xanthurenic acid, a putative endogenous group II metabotropic glutamate receptor agonist, on sensory transmission in the thalamus. Neuropharmacology, 2 Apr 2012 (doi: 10.1016/j.neuropharm.2012.03.009). ArticleCASPubMed Google Scholar
Fazio, F. et al. Cinnabarinic acid, an endogenous metabolite of the kynurenine pathway, activates type 4 metabotropic glutamate receptors. Mol. Pharmacol.81, 643–656 (2012). ArticleCASPubMed Google Scholar
Giles, G. I., Collins, C. A., Stone, T. W. & Jacob, C. Electrochemical and in vitro evaluation of the redox-properties of kynurenine species. Biochem. Biophys. Res. Commun.300, 719–724 (2003). ArticleCASPubMed Google Scholar
Goldstein, L. E. et al. 3-Hydroxykynurenine and 3-hydroxyanthranilic acid generate hydrogen peroxide and promote α-crystallin cross-linking by metal ion reduction. Biochemistry39, 7266–7275 (2000). ArticleCASPubMed Google Scholar
Christen, S., Peterhans, E. & Stocker, R. Antioxidant activities of some tryptophan metabolites: possible implication for inflammatory diseases. Proc. Natl Acad. Sci. USA87, 2506–2510 (1990). Key paper linking metabolites of the kynurenine pathway to redox processes and inflammatory conditions. ArticleCASPubMedPubMed Central Google Scholar
Lapin, I. P. Stimulant and convulsive effects of kynurenines injected into brain ventricles in mice. J. Neural Transm.42, 37–43 (1978). ArticleCASPubMed Google Scholar
Stone, T. W. & Perkins, M. N. Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur. J. Pharmacol.72, 411–412 (1981). ArticleCASPubMed Google Scholar
de Carvalho, L. P., Bochet, P. & Rossier, J. The endogenous agonist quinolinic acid and the non endogenous homoquinolinic acid discriminate between NMDAR2 receptor subunit. Neurochem. Int.28, 445–452 (1996). ArticleCASPubMed Google Scholar
Ríos, C. & Santamaría, A. Quinolinic acid is a potent lipid peroxidant in rat brain homogenates. Neurochem. Res.16, 1139–1143 (1991). ArticlePubMed Google Scholar
Stípek, S., Stastný, F., Pláteník, J., Crkovská, J. & Zima, T. The effect of quinolinate on rat brain lipid peroxidation is dependent on iron. Neurochem. Int.30, 233–237 (1997). ArticlePubMed Google Scholar
Pláteník, J., Stopka, P., Vejrazka, M. & Stípek, S. Quinolinic acid–iron (II) complexes: slow autoxidation, but enhanced hydroxyl radical production in the fenton reaction. Free Radic. Res.34, 445–459 (2001). ArticlePubMed Google Scholar
St'astny, F., Hinoi, E., Ogita, K. & Yoneda, Y. Ferrous iron modulates quinolinate-mediated [3H]MK-801 binding to rat brain synaptic membranes in the presence of glycine and spermidine. Neurosci. Lett.262, 105–108 (1999). ArticleCASPubMed Google Scholar
Baran, H. & Schwarcz, R. Presence of 3-hydroxyanthranilic acid in rat tissues and evidence for its production from anthranilic acid in the brain. J. Neurochem.55, 738–744 (1990). ArticleCASPubMed Google Scholar
Guidetti, P., Walsh, J. L. & Schwarcz, R. A fluorimetric assay for the determination of anthranilic acid in biological materials. Anal. Biochem.220, 181–184 (1994). ArticleCASPubMed Google Scholar
Gobaille, S. et al. Xanthurenic acid distribution, transport, accumulation and release in the rat brain. J. Neurochem.105, 982–993 (2008). ArticleCASPubMed Google Scholar
Moroni, F., Russi, P., Lombardi, G., Beni, M. & Carlá, V. Presence of kynurenic acid in the mammalian brain. J. Neurochem.51, 177–180 (1988). ArticleCASPubMed Google Scholar
Saito, K., Markey, S. P. & Heyes, M. P. Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse. Neuroscience51, 25–39 (1992). ArticleCASPubMed Google Scholar
Smythe, G. A. et al. ECNI GC-MS analysis of picolinic and quinolinic acids and their amides in human plasma, CSF, and brain tissue. Adv. Exp. Med. Biol.527, 705–712 (2003). ArticleCASPubMed Google Scholar
Turski, W. A. et al. Identification and quantification of kynurenic acid in human brain tissue. Brain Res.454, 164–169 (1988). ArticleCASPubMed Google Scholar
Dang, Y., Dale, W. E. & Brown, O. R. Comparative effects of oxygen on indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase of the kynurenine pathway. Free Radic. Biol. Med.28, 615–624 (2000). ArticleCASPubMed Google Scholar
Gál, E. M. & Sherman, A. D. L-Kynurenine: its synthesis and possible regulatory function in brain. Neurochem. Res.5, 223–239 (1980). ArticlePubMed Google Scholar
Speciale, C. & Schwarcz, R. Uptake of kynurenine into rat brain slices. J. Neurochem.54, 156–163 (1990). ArticleCASPubMed Google Scholar
Guidetti, P., Eastman, C. L. & Schwarcz, R. Metabolism of [5-3H]kynurenine in the rat brain in vivo: evidence for the existence of a functional kynurenine pathway. J. Neurochem.65, 2621–2632 (1995). ArticleCASPubMed Google Scholar
Guillemin, G. J. et al. Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection. J. Neurochem.78, 842–853 (2001). ArticleCASPubMed Google Scholar
Fukui, S., Schwarcz, R., Rapoport, S. I., Takada, Y. & Smith, Q. R. Blood–brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J. Neurochem.56, 2007–2017 (1991). ArticleCASPubMed Google Scholar
Speciale, C., Ungerstedt, U. & Schwarcz, R. Production of extracellular quinolinic acid in the striatum studied by microdialysis in unanesthetized rats. Neurosci. Lett.104, 345–350 (1989). ArticleCASPubMed Google Scholar
Speciale, C. et al. Determination of extracellular kynurenic acid in the striatum of unanesthetized rats: effect of aminooxyacetic acid. Neurosci. Lett.116, 198–203 (1990). ArticleCASPubMed Google Scholar
Speciale, C. & Schwarcz, R. On the production and disposition of quinolinic acid in rat brain and liver slices. J. Neurochem.60, 212–218 (1993). ArticleCASPubMed Google Scholar
Gramsbergen, J. B. et al. Brain-specific modulation of kynurenic acid synthesis in the rat. J. Neurochem.69, 290–298 (1997). ArticleCASPubMed Google Scholar
Hodgkins, P. S. & Schwarcz, R. Interference with cellular energy metabolism reduces kynurenic acid formation in rat brain slices: reversal by lactate and pyruvate. Eur. J. Neurosci.10, 1986–1994 (1998). ArticleCASPubMed Google Scholar
Hodgkins, P. S., Wu, H. Q., Zielke, H. R. & Schwarcz, R. 2-Oxoacids regulate kynurenic acid production in the rat brain: studies in vitro and in vivo. J. Neurochem.72, 643–651 (1999). ArticleCASPubMed Google Scholar
Rassoulpour, A., Wu, H.-Q., Poeggeler, B. & Schwarcz, R. Systemic D-amphetamine administration causes a reduction of kynurenic acid levels in rat brain. Brain Res.802, 111–118 (1998). ArticleCASPubMed Google Scholar
Uwai, Y., Honjo, H. & Iwamoto, K. Interaction and transport of kynurenic acid via human organic anion transporters hOAT1 and hOAT3. Pharmacol. Res.65, 254–260 (2012). ArticleCASPubMed Google Scholar
Foster, A. C., Miller, L. P., Oldendorf, W. H. & Schwarcz, R. Studies on the disposition of quinolinic acid after intracerebral or systemic administration in the rat. Exp. Neurol.84, 428–440 (1984). ArticleCASPubMed Google Scholar
Salter, M. & Pogson, C. I. The role of tryptophan 2,3-dioxygenase in the hormonal control of tryptophan metabolism in isolated rat liver cells. Biochem. J.229, 499–504 (1985). ArticleCASPubMedPubMed Central Google Scholar
Espey, M. G. & Namboodiri, M. A. A. Selective metabolism of kynurenine in the spleen in the absence of indoleamine 2,3-dioxygenase induction. Immunol. Lett.71, 67–72 (2000). ArticleCASPubMed Google Scholar
Belladonna, M. L. et al. Kynurenine pathway enzymes in dendritic cells initiate tolerogenesis in the absence of functional IDO. J. Immunol.177, 130–137 (2006). ArticleCASPubMed Google Scholar
Huang, L., Baban, B., Johnson, B. A. 3rd & Mellor, A. L. Dendritic cells, indoleamine 2,3 dioxygenase and acquired immune privilege. Int. Rev. Immunol.29, 133–155 (2010). ArticleCASPubMedPubMed Central Google Scholar
Saito, K. et al. Kynurenine pathway enzymes in brain: respones to ischemic brain injury versus systemic immune activation. J. Neurochem.61, 2061–2070 (1993). ArticleCASPubMed Google Scholar
Schwarcz, R. & Pellicciari, R. Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J. Pharmacol. Exp. Ther.303, 1–10 (2002). ArticleCASPubMed Google Scholar
Yu, P. et al. Biochemical and phenotypic abnormalities in kynurenine aminotransferase II-deficient mice. Mol. Cell. Biol.24, 6919–6930 (2004). ArticleCASPubMedPubMed Central Google Scholar
Carpenedo, R. et al. Presynaptic kynurenate-sensitive receptors inhibit glutamate release. Eur. J. Neurosci.13, 2141–2147 (2001). ArticleCASPubMed Google Scholar
Rassoulpour, A., Wu, H. Q., Ferré, S. & Schwarcz, R. Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatum. J. Neurochem.93, 762–765 (2005). ArticleCASPubMed Google Scholar
Amori, L. et al. Specific inhibition of kynurenate synthesis enhances extracellular dopamine levels in the rodent striatum. Neuroscience159, 196–203 (2009). ArticleCASPubMed Google Scholar
Zmarowski, A. et al. Astrocyte-derived kynurenic acid modulates basal and evoked cortical acetylcholine release. Eur. J. Neurosci.29, 529–538 (2009). ArticleCASPubMed Google Scholar
Albuquerque, E. X., Pereira, E. F., Alkondon, M. & Rogers, S. W. Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol. Rev.89, 73–120 (2009). ArticleCASPubMed Google Scholar
Shepard, P. D., Joy, B., Clerkin, L. & Schwarcz, R. Micromolar brain levels of kynurenic acid are associated with a disruption of auditory sensory gating in the rat. Neuropsychopharmacology28, 1454–1462 (2003). ArticleCASPubMed Google Scholar
Erhardt, S., Schwieler, L., Emanuelsson, C. & Geyer, M. Endogenous kynurenic acid disrupts prepulse inhibition. Biol. Psychiatry56, 255–260 (2004). ArticleCASPubMed Google Scholar
Chess, A. C., Simoni, M. K., Alling, T. E. & Bucci, D. J. Elevations of endogenous kynurenic acid produce spatial working memory deficits. Schizophr. Bull.33, 797–804 (2007). ArticlePubMed Google Scholar
Chess, A. C., Landers, A. M. & Bucci, D. J. L-kynurenine treatment alters contextual fear conditioning and context discrimination but not cue-specific fear conditioning. Behav. Brain Res.201, 325–331 (2009). ArticleCASPubMed Google Scholar
Linderholm, K. R. et al. Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: a pharmacological analysis. Neuropharmacology53, 918–924 (2007). ArticleCASPubMed Google Scholar
Erhardt, S., Oberg, H., Mathe, J. M. & Engberg, G. Pharmacological elevation of endogenous kynurenic acid levels activates nigral dopamine neurons. AminoAcids20, 353–362 (2001). ArticleCAS Google Scholar
Potter, M. C. et al. Reduction of endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior. Neuropsychopharmacology35, 1734–1742 (2010). ArticleCASPubMedPubMed Central Google Scholar
Pocivavsek, A. et al. Fluctuations in endogenous kynurenic acid control hippocampal glutamate and memory. Neuropsychopharmacology36, 2357–2367 (2011). This article is the first to demonstrate that acute upregulation of endogenous KYNA levels worsens, whereas acute downregulation ameliorates, cognitive function. ArticleCASPubMedPubMed Central Google Scholar
Giorgini, F. et al. Generation and initial characterization of homozygous and heterozygous kynurenine 3-monooxygenase knockout mice. Soc. Neurosci. Abstr. 466.01 (Washington, DC, 12–16 Nov 2011).
Baban, B. et al. Indoleamine 2,3-dioxygenase expression is restricted to fetal trophoblast giant cells during murine gestation and is maternal genome specific. J. Reprod. Immunol.61, 67–77 (2004). ArticleCASPubMed Google Scholar
Kanai, M. et al. Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice. Mol. Brain2, 8 (2009). ArticleCASPubMedPubMed Central Google Scholar
Schwarcz, R., Whetsell, W. O. Jr & Mangano, R. M. Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science219, 316–318 (1983). ArticleCASPubMed Google Scholar
Foster, A. C., Vezzani, A., French, E. D. & Schwarcz, R. Kynurenic acid blocks neurotoxicity and seizures induced in rats by the related brain metabolite quinolinic acid. Neurosci. Lett.48, 273–278 (1984). In this report, the authors describe the excitotoxic effect of QUIN and the distinct neuroprotective properties of KYNA, suggesting a role for both of these metabolites in the pathophysiology of neurodegenerative diseases and seizure disorders. ArticleCASPubMed Google Scholar
Simon, R. P., Swan, J. H., Griffiths, T. & Meldrum, B. S. Blockade of _N_-methyl-D-aspartate receptors may protect against ischemic damage in the brain. Science226, 850–852 (1984). ArticleCASPubMed Google Scholar
Wieloch, T. Hypoglycemia-induced neuronal damage prevented by an _N_-methyl-D-aspartate antagonist. Science230, 681–683 (1985). ArticleCASPubMed Google Scholar
Schwarcz, R., Foster, A. C., French, E. D., Whetsell, W. O. Jr & Köhler, C. Excitotoxic models for neurodegenerative disorders. Life Sci.35, 19–32 (1984). ArticleCASPubMed Google Scholar
Coyle, J. T. & Schwarcz, R. Lesion of striatal neurones with kainic acid provides a model for Huntington's chorea. Nature263, 244–246 (1976). ArticleCASPubMed Google Scholar
Guidetti, P., Luthi-Carter, R. E., Augood, S. J. & Schwarcz, R. Neostriatal and cortical quinolinate levels are increased in early grade Huntington's disease. Neurobiol. Dis.17, 455–461 (2004). ArticleCASPubMed Google Scholar
Tai, Y. F. et al. Microglial activation in presymptomatic Huntington's disease gene carriers. Brain130, 1759–1766 (2007). ArticlePubMed Google Scholar
Whetsell, W. O. Jr & Schwarcz, R. Prolonged exposure to submicromolar concentrations of quinolinic acid causes excitotoxic damage in organotypic cultures of rat corticostriatal system. Neurosci. Lett.97, 271–275 (1989). ArticleCASPubMed Google Scholar
Kerr, S. J., Armati, P. J., Guillemin, G. J. & Brew, B. J. Chronic exposure of human neurons to quinolinic acid results in neuronal changes consistent with AIDS dementia complex. AIDS12, 355–363 (1998). ArticleCASPubMed Google Scholar
Pearson, S. J. & Reynolds, G. P. Increased brain concentrations of a neurotoxin, 3-hydroxykynurenine, in Huntington's disease. Neurosci. Lett.144, 199–201 (1992). ArticleCASPubMed Google Scholar
Okuda, S., Nishiyama, N., Saito, H. & Katsuki, H. 3-Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. J. Neurochem.70, 299–307 (1998). ArticleCASPubMed Google Scholar
Guidetti, P. & Schwarcz, R. 3-Hydroxykynurenine potentiates quinolinate but not NMDA toxicity in the rat striatum. Eur. J. Neurosci.11, 3857–3863 (1999). ArticleCASPubMed Google Scholar
Chiarugi, A., Meli, E. & Moroni, F. Similarities and differences in the neuronal death processes activated by 3OH-kynurenine and quinolinic acid. J. Neurochem.77, 1310–1318 (2001). ArticleCASPubMed Google Scholar
Beal, M. F. et al. Kynurenic acid concentrations are reduced in Huntington's disease cerebral cortex. J. Neurol. Sci.108, 80–87 (1992). ArticleCASPubMed Google Scholar
Sapko, M. T. et al. Endogenous kynurenate controls the vulnerability of striatal neurons to quinolinate: implications for Huntington's disease. Exp. Neurol.197, 31–40 (2006). ArticleCASPubMed Google Scholar
Guidetti, P. et al. Elevated brain 3-hydroxykynurenine and quinolinate levels in Huntington disease mice. Neurobiol. Dis.23, 190–197 (2006). ArticleCASPubMed Google Scholar
Guidetti, P., Reddy, P. H., Tagle, D. A. & Schwarcz, R. Early kynurenergic impairment in Huntington's disease and in a transgenic animal model. Neurosci. Lett.283, 233–235 (2000). ArticleCASPubMed Google Scholar
Giorgini, F., Guidetti, P., Nguyen, Q., Bennett, S. C. & Muchowski, P. J. A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Nature Genet.37, 526–531 (2005). ArticleCASPubMed Google Scholar
Giorgini, F. et al. Histone deacetylase inhibition modulates kynurenine pathway activation in yeast, microglia, and mice expressing a mutant huntingtin fragment. J. Biol. Chem.283, 7390–7400 (2008). ArticleCASPubMed Google Scholar
Campesan, S. et al. The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington's disease. Curr. Biol.21, 961–966 (2011). ArticleCASPubMedPubMed Central Google Scholar
Ogawa, T. et al. Kynurenine pathway abnormalities in Parkinson's disease. Neurology42, 1702–1706 (1992). ArticleCASPubMed Google Scholar
Guillemin, G. J., Brew, B. J., Noonan, C. E., Takikawa, O. & Cullen, K. M. Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer's disease hippocampus. Neuropathol. Appl. Neurobiol.31, 395–404 (2005). ArticleCASPubMed Google Scholar
Bonda, D. J. et al. Indoleamine 2,3-dioxygenase and 3-hydroxykynurenine modifications are found in the neuropathology of Alzheimer's disease. Redox Rep.15, 161–168 (2010). ArticleCASPubMed Google Scholar
Baran, H., Gramer, M., Honack, D. & Löscher, W. Systemic administration of kainate induces marked increases of endogenous kynurenic acid in various brain regions and plasma of rats. Eur. J. Pharmacol.286, 167–175 (1995). ArticleCASPubMed Google Scholar
Lehrmann, E. et al. Glial activation precedes seizures and hippocampal neurodegeneration in measles virus-infected mice. Epilepsia49 (Suppl. 2), 13–23 (2008). ArticlePubMed Google Scholar
Wu, H. Q. & Schwarcz, R. Seizure activity causes elevation of endogenous extracellular kynurenic acid in the rat brain. Brain Res. Bull.39, 155–162 (1996). ArticleCASPubMed Google Scholar
Chugani, D. C. α-methyl-L-tryptophan: mechanisms for tracer localization of epileptogenic brain regions. Biomark. Med.5, 567–575 (2011). ArticleCASPubMed Google Scholar
Heyes, M. P., Papagapiou, M., Leonard, C., Markey, S. P. & Auer, R. N. Effects of profound insulin-induced hypoglycemia on quinolinic acid in hippocampus and plasma. Adv. Exp. Med. Biol.294, 679–682 (1991). ArticleCASPubMed Google Scholar
Saito, K., Nowak, T. S. J., Markey, S. P. & Heyes, M. P. Mechanism of delayed increases in kynurenine pathway metabolism in damaged brain regions following transient cerebral ischemia. J. Neurochem.60, 180–192 (1993). ArticleCASPubMed Google Scholar
Ceresoli-Borroni, G. & Schwarcz, R. Neonatal asphyxia in rats: acute effects on cerebral kynurenine metabolism. Pediatr. Res.50, 231–235 (2001). ArticleCASPubMed Google Scholar
Blight, A. R., Saito, K. & Heyes, M. P. Increased levels of the excitotoxin quinolinic acid in spinal cord following contusion injury. Brain Res.632, 314–316 (1993). ArticleCASPubMed Google Scholar
Moroni, F. Tryptophan metabolism and brain function: focus on kynurenine and other indole metabolites. Eur. J. Pharmacol.375, 87–100 (1999). ArticleCASPubMed Google Scholar
Németh, H., Toldi, J. & Vécsei, L. Kynurenines, Parkinson's disease and other neurodegenerative disorders: preclinical and clinical studies. J. Neural Transm.70, 285–304 (2006). Google Scholar
Chen, Y. & Guillemin, G. J. Kynurenine pathway metabolites in humans: disease and healthy states. Int. J. Tryptophan Res.2, 1–19 (2009). ArticlePubMedPubMed Central Google Scholar
Miu, J., Ball, H. J., Mellor, A. L. & Hunt, N. H. Effect of indoleamine dioxygenase-1 deficiency and kynurenine pathway inhibition on murine cerebral malaria. Int. J. Parasitol.39, 363–370 (2009). ArticleCASPubMed Google Scholar
Wang, Y. et al. Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nature Med.16, 279–285 (2010). ArticleCASPubMed Google Scholar
Rodgers, J., Stone, T. W., Barrett, M. P., Bradley, B. & Kennedy, P. G. Kynurenine pathway inhibition reduces central nervous system inflammation in a model of human African trypanosomiasis. Brain132, 1259–1267 (2009). ArticlePubMedPubMed Central Google Scholar
Perry, V. H., Nicoll, J. A. & Holmes, C. Microglia in neurodegenerative disease. Nature Rev. Neurol.6, 193–201 (2010). Article Google Scholar
Steinman, L. Elaborate interactions between the immune and nervous systems. Nature Immunol.5, 575–581 (2004). ArticleCAS Google Scholar
Guillemin, G. J., Smith, D. G., Smythe, G. A., Armati, P. J. & Brew, B. J. Expression of the kynurenine pathway enzymes in human microglia and macrophages. Adv. Exp. Med. Biol.527, 105–112 (2003). ArticleCASPubMed Google Scholar
Heyes, M. P. et al. Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. Brain115, 1249–1273 (1992). This paper links inflammatory processes in the brain to a dysfunctional cerebral kynurenine pathway, suggesting that normalization of brain kynurenines may provide novel therapies for neurovirological and other neuroimmune diseases. ArticlePubMed Google Scholar
Heyes, M. P., Mefford, I. N., Quearry, B. J., Dedhia, M. & Lackner, A. Increased ratio of quinolinic acid to kynurenic acid in cerebrospinal fluid of D retrovirus-infected rhesus macaques: relationship to clinical and viral status. Ann. Neurol.27, 666–675 (1990). ArticleCASPubMed Google Scholar
Alberati-Giani, D., Ricciardi-Castagnoli, P., Köhler, C. & Cesura, A. M. Regulation of the kynurenine metabolic pathway by interferon-γ in murine clone macrophages and microglial cells. J. Neurochem.66, 996–1004 (1996). ArticleCASPubMed Google Scholar
Lapin, I. P. Kynurenines as probable participants of depression. Pharmakopsychiatr. Neuropsychopharmakol.6, 273–279 (1973). ArticleCASPubMed Google Scholar
Maes, M. et al. Depressive and anxiety symptoms in the early puerperium are related to increased degradation of tryptophan into kynurenine, a phenomenon which is related to immune activation. Life Sci.71, 1837–1848 (2002). ArticleCASPubMed Google Scholar
Capuron, L. et al. Interferon-alpha-induced changes in tryptophan metabolism: relationship to depression and paroxetine treatment. Biol. Psychiatry54, 906–914 (2003). ArticleCASPubMed Google Scholar
Raison, C. L. et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-α: relationship to CNS immune responses and depression. Mol. Psychiatry15, 393–403 (2010). ArticleCASPubMed Google Scholar
O'Connor, J. C. et al. Interferon-γ and tumor necrosis factor-α mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guérin. J. Neurosci.29, 4200–4209 (2009). In this paper, the authors demonstrate that the delayed emergence of depressive-like behaviour in mice is caused by the cytokine-induced induction of IDO. ArticleCASPubMedPubMed Central Google Scholar
O'Connor, J. C. et al. Induction of IDO by bacille Calmette-Guérin is responsible for development of murine depressive-like behavior. J. Immunol.182, 3202–3212 (2009). ArticleCASPubMed Google Scholar
Smith, A. K. et al. Association of a polymorphism in the indoleamine- 2,3-dioxygenase gene and interferon-α-induced depression in patients with chronic hepatitis C. Mol. Psychiatry 21 Jun 2011 (doi: 10.1038/mp.2011.67). ArticleCASPubMedPubMed Central Google Scholar
Manuelpillai, U. et al. Identification of kynurenine pathway enzyme mRNAs and metabolites in human placenta: up-regulation by inflammatory stimuli and with clinical infection. Am. J. Obstet. Gynecol.192, 280–288 (2005). ArticleCASPubMed Google Scholar
Kohl, C. et al. Measurement of tryptophan, kynurenine and neopterin in women with and without postpartum blues. J. Affect. Disord.86, 135–142 (2005). ArticleCASPubMed Google Scholar
Si, X., Miguel-Hidalgo, J. J., O'Dwyer, G., Stockmeier, C. A. & Rajkowska, G. Age-dependent reductions in the level of glial fibrillary acidic protein in the prefrontal cortex in major depression. Neuropsychopharmacology29, 2088–2096 (2004). ArticleCASPubMed Google Scholar
Czeh, B., Simon, M., Schmelting, B., Hiemke, C. & Fuchs, E. Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology31, 1616–1626 (2006). ArticleCASPubMed Google Scholar
Tynan, R. J. et al. Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions. Brain. Behav. Immun.24, 1058–1068 (2010). ArticleCASPubMed Google Scholar
Steiner, J. et al. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J. Neuroinflammation8, 94 (2011). ArticleCASPubMedPubMed Central Google Scholar
Hanson, N. D., Owens, M. J. & Nemeroff, C. B. Depression, antidepressants, and neurogenesis: a critical reappraisal. Neuropsychopharmacology36, 2589–2602 (2011). ArticlePubMedPubMed Central Google Scholar
Zunszain, P. A. et al. Interleukin-1β: A new regulator of the kynurenine pathway affecting human hippocampal neurogenesis. Neuropsychopharmacology37, 939–949 (2011). ArticleCASPubMedPubMed Central Google Scholar
Skolnick, P., Popik, P. & Trullas, R. Glutamate-based antidepressants: 20 years on. Trends Pharmacol. Sci.30, 563–569 (2009). ArticleCASPubMed Google Scholar
Laugeray, A. et al. Peripheral and cerebral metabolic abnormalities of the tryptophan-kynurenine pathway in a murine model of major depression. Behav. Brain Res.210, 84–91 (2010). ArticleCASPubMed Google Scholar
Murrough, J. W., Iacoviello, B., Neumeister, A., Charney, D. S. & Iosifescu, D. V. Cognitive dysfunction in depression: neurocircuitry and new therapeutic strategies. Neurobiol. Learn. Mem.96, 553–563 (2011). ArticleCASPubMed Google Scholar
Frazer, A., Pandey, G. N. & Mendels, J. Metabolism of tryptophan in depressive disease. Arch. Gen. Psychiatry29, 528–535 (1973). ArticleCASPubMed Google Scholar
Krystal, J. H. et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Arch. Gen. Psychiatry51, 199–214 (1994). ArticleCASPubMed Google Scholar
Lahti, A. C., Koffel, B., LaPorte, D. & Tamminga, C. A. Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology13, 9–19 (1995). ArticleCASPubMed Google Scholar
Anis, N. A., Berry, S. C., Burton, N. R. & Lodge, D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by _N_-methyl-aspartate. Br. J. Pharmacol.79, 565–575 (1983). ArticleCASPubMedPubMed Central Google Scholar
Schwarcz, R. et al. Kynurenic acid: a potential pathogen in brain disorders. Ann. NY Acad. Sci.648, 140–153 (1992). ArticleCASPubMed Google Scholar
Erhardt, S. et al. Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci. Lett.313, 96–98 (2001). ArticleCASPubMed Google Scholar
Schwarcz, R. et al. Increased cortical kynurenate content in schizophrenia. Biol. Psychiatry50, 521–530 (2001). This is the first direct evidence linking increased cerebral KYNA levels to the pathophysiology of schizophrenia. ArticleCASPubMed Google Scholar
Ceresoli-Borroni, G., Rassoulpour, A., Wu, H. Q., Guidetti, P. & Schwarcz, R. Chronic neuroleptic treatment reduces endogenous kynurenic acid levels in rat brain. J. Neural Transm.113, 1355–1365 (2006). ArticleCASPubMed Google Scholar
Sathyasaikumar, K. V. et al. Impaired kynurenine pathway metabolism in the prefrontal cortex of individuals with schizophrenia. Schizophr. Bull.37, 1147–1156 (2011). ArticlePubMed Google Scholar
Wonodi, I. et al. Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes. Arch. Gen. Psychiatry68, 665–674 (2011). ArticleCASPubMed Google Scholar
Miller, C. L., Llenos, I. C., Dulay, J. R. & Weis, S. Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder. Brain Res. 1073–1074, 25–37 (2006).
Miller, C. L. et al. Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia. Neurobiol. Dis.15, 618–629 (2004). ArticleCASPubMed Google Scholar
Linderholm, K. R. et al. Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. Schizophr. Bull.38, 426–432 (2010). ArticlePubMedPubMed Central Google Scholar
Potvin, S. et al. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol. Psychiatry63, 801–808 (2008). ArticleCASPubMed Google Scholar
Müller, N. & Schwarz, M. Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission. Neurotox. Res.10, 131–148 (2006). ArticlePubMed Google Scholar
Erhardt, S. & Engberg, G. Increased phasic activity of dopaminergic neurones in the rat ventral tegmental area following pharmacologically elevated levels of endogenous kynurenic acid. Acta Physiol. Scand.175, 45–53 (2002). ArticleCASPubMed Google Scholar
Goto, Y., Yang, C. R. & Otani, S. Functional and dysfunctional synaptic plasticity in prefrontal cortex: roles in psychiatric disorders. Biol. Psychiatry67, 199–207 (2010). ArticlePubMed Google Scholar
Alexander, K. S., Wu, H. Q., Schwarcz, R. & Bruno, J. P. Acute elevations of brain kynurenic acid impair cognitive flexibility: normalization by the α7 positive modulator galantamine. Psychopharmacol. (Berl.)220, 627–637 (2012). ArticleCAS Google Scholar
Alexander, K. et al. Perinatal elevations of kynurenic acid dysregulate prefrontal glutamate release and produce set-shifting deficits in adults: a new model of schizophrenia. Soc. Neurosci. Abstr. 163.23 (Washington, DC, 12–16 Nov 2011).
Trecartin, K. V. & Bucci, D. J. Administration of kynurenine during adolescence, but not during adulthood, impairs social behavior in rats. Schizophr. Res.133, 156–158 (2011). ArticlePubMedPubMed Central Google Scholar
Akagbosu, C. O., Evans, G. C., Gulick, D., Suckow, R. F. & Bucci, D. J. Exposure to kynurenic acid during adolescence produces memory deficits in adulthood. Schizophr. Bull. 20 Dec 2010 (doi: 10.1093/schbul/sbq151). ArticlePubMedPubMed Central Google Scholar
Pocivavsek, A., Wu, H. Q., Elmer, G. I., Bruno, J. P. & Schwarcz, R. Pre- and postnatal exposure to kynurenine causes cognitive deficits in adulthood. Eur. J. Neurosci.35, 1605–1612 (2012). ArticlePubMedPubMed Central Google Scholar
Aoyama, N. et al. Association study between kynurenine 3-monooxygenase gene and schizophrenia in the Japanese population. Genes Brain Behav.5, 364–368 (2006). ArticleCASPubMed Google Scholar
McFarlane, H. G. et al. Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes Brain Behav.7, 152–163 (2008). ArticleCASPubMed Google Scholar
Justinova, Z. et al. Kynurenine 3-monooxygenase inhibition by Ro 61-8048 blocks self-administration of the psychoactive ingredient of marijuana in squirrel monkeys and prevents relapse. Soc. Neurosci. Abstr. 911.12 (Washington, DC, 12–16 Nov 2011).
Olsson, S. K. et al. Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder. J. Psychiatry Neurosci.35, 195–199 (2010). ArticlePubMedPubMed Central Google Scholar
Pellicciari, R. et al. Modulators of the kynurenine pathway of tryptophan metabolism. Synthesis and preliminary biological evaluation of (S)-4-(ethylsulfonyl)benzoylalanine, a potent and selective kynurenine aminotransferase II (KAT II) inhibitor. ChemMedChem.1, 528–531 (2006). ArticleCASPubMed Google Scholar
Chapin, D. S., Campbell, B., Strick, C. A. & Kozak, R. The impact of a KATII inhibitor on performance in the rat sustained attentional task (SAT) and conditioned avoidance responding (CAR). Soc. Neurosci. Abstr. 472.16 (San Diego, CA, 13–17 Nov 2010).
Kozak, R. et al. A novel and systemically available KAT II inhibitor protects the α7 nicotinic acetylcholine receptor against blockade by kynurenic acid. Soc. Neurosci. Abstr. 767.30 (San Diego, CA, 13–17 Nov 2010).
Abbott, A. et al. Inhibition of kynurenine aminotransferase ii (kat ii) protects against ketamine-induced cognitive impairment and improves spatial working memory. Soc. Neurosci. Abstr. 472.18 (San Diego, CA, 13–17 Nov 2010).
Koshy Cherian, A. et al. A novel systemically-available kynurenine aminotransferase II (KATII) inhibitor normalizes prefrontal glutamatergic activity in an animal model of schizophrenia. Soc. Neurosci. Abstr. 568.13 (Washington, DC, 12–16 Nov 2011).
Connick, J. H. et al. Nicotinylalanine increases cerebral kynurenic acid content and has anticonvulsant activity. Gen. Pharmacol.23, 235–239 (1992). ArticleCASPubMed Google Scholar
Carpenedo, R. et al. Inhibitors of kynurenine hydroxylase and kynureninase increase cerebral formation of kynurenate and have sedative and anticonvulsant activities. Neuroscience61, 237–244 (1994). ArticleCASPubMed Google Scholar
Speciale, C. et al. (R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats. Eur. J. Pharmacol.315, 263–267 (1996). ArticleCASPubMed Google Scholar
Röver, S., Cesura, A. M., Huguenin, P., Kettler, R. & Szente, A. Synthesis and biochemical evaluation of _N_-(4-phenylthiazol-2-yl)benzenesulfonamides as high-affinity inhibitors of kynurenine 3-hydroxylase. J. Med. Chem.40, 4378–4385 (1997). ArticlePubMed Google Scholar
Cozzi, A., Carpenedo, R. & Moroni, F. Kynurenine hydroxylase inhibitors reduce ischemic brain damage: studies with (_m_-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxyl-[-N-4-(nitrophenyl)thiazol-2YL-benzenesulfonamide (Ro 61-8048) in models of focal or global brain ischemia. _J. Cereb. Blood Flow Metab._ **19**, 771–777 (1999). **Using well-established animal models of cerebral ischaemia, this is the first paper to demonstrate impressive neuroprotection following systemic administration of a KMO inhibitor.** ArticleCASPubMed Google Scholar
Gregoire, L. et al. Prolonged kynurenine 3-hydroxylase inhibition reduces development of levodopa-induced dyskinesias in parkinsonian monkeys. Behav. Brain Res.186, 161–167 (2008). ArticleCASPubMed Google Scholar
Clark, C. J. et al. Prolonged survival of a murine model of cerebral malaria by kynurenine pathway inhibition. Infect. Immun.73, 5249–5251 (2005). ArticleCASPubMedPubMed Central Google Scholar
Zwilling, D. et al. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell145, 863–874 (2011). The authors show that relatively moderate, chronic peripheral KMO inhibition, by indirectly increasing brain KYNA formation, affords neuroprotection in animal models of Huntington's and Alzheimer's disease. ArticleCASPubMedPubMed Central Google Scholar
Owe-Young, R. et al. Kynurenine pathway metabolism in human blood–brain–barrier cells: implications for immune tolerance and neurotoxicity. J. Neurochem.105, 1346–1357 (2008). ArticleCASPubMed Google Scholar
Chiarugi, A. & Moroni, F. Quinolinic acid formation in immune-activated mice: studies with (_m_-nitrobenzoyl)-alanine (_m_NBA) and 3,4-dimethoxy-[-N-4-(-3-nitrophenyl) thiazol-2yl]-benzenesulfonamide (Ro 61-8048), two potent and selective inhibitors of kynurenine hydroxylase. Neuropharmacology38, 1225–1233 (1999). ArticleCASPubMed Google Scholar
Prendergast, G. C., Chang, M. Y., Mandik-Nayak, L., Metz, R. & Muller, A. J. Indoleamine 2,3-dioxygenase as a modifier of pathogenic inflammation in cancer and other inflammation-associated diseases. Curr. Med. Chem.18, 2257–2262 (2011). ArticleCASPubMedPubMed Central Google Scholar
Combs, A. P. et al. 1,2,5-Oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase. US Patent Application #2012/0058079 (2012).
Pilotte, L. et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc. Natl Acad. Sci. USA109, 2497–2502 (2012). ArticleCASPubMedPubMed Central Google Scholar
Sakurai, K., Zou, J.-P., Tschetter, J. R., Ward, J. M. & Shearer, G. M. Effect of indoleamine 2,3-dioxygenase on induction of experimental autoimmune encephalomyelitis. J. Neuroimmunol.129, 186–196 (2002). ArticleCASPubMed Google Scholar
Mellor, A. L. & Munn, D. H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nature Rev. Immunol.4, 762–774 (2004). ArticleCAS Google Scholar
Chiarugi, A. et al. Comparison of the neurochemical and behavioral effects resulting from the inhibition of kynurenine hydroxylase and/or kynureninase. J. Neurochem.65, 1176–1183 (1995). ArticleCASPubMed Google Scholar
Madge, D. J., Hazelwood, R., Iyer, R., Jones, H. T. & Salter, M. Novel tryptophan dioxygenase inhibitors and combined tryptophan dioxygenase/5-HT reuptake inhibitors. Bioorg. Med. Chem. Lett.6, 857–860 (1996). ArticleCAS Google Scholar
Parli, C. J., Krieter, P. & Schmidt, B. Metabolism of 6-chlorotryptophan to 4-chloro-3-hydroxyanthranilic acid: a potent inhibitor of 3-hydroxyanthranilic acid oxidase. Arch. Biochem. Biophys.203, 161–166 (1980). ArticleCASPubMed Google Scholar
Lehrmann, E., Molinari, A., Speciale, C. & Schwarcz, R. Immunohistochemical visualization of newly formed quinolinate in the normal and excitotoxically lesioned rat striatum. Exp. Brain Res.141, 389–397 (2001). ArticleCASPubMed Google Scholar
Yates, J. R., Heyes, M. P. & Blight, A. R. 4-chloro-3-hydroxyanthranilate reduces local quinolinic acid synthesis, improves functional recovery, and preserves white matter after spinal cord injury. J. Neurotrauma23, 866–881 (2006). ArticlePubMed Google Scholar
Uemura, T. & Hirai, K. Kynurenine 3-monooxygenase activity of rat brain mitochondria determined by high performance liquid chromatography with electrochemical detection. Adv. Exp. Med. Biol.294, 531–534 (1991). ArticleCASPubMed Google Scholar
Minakata, K., Fukushima, K., Nakamura, M. & Iwahashi, H. Effect of some naturally occurring iron ion chelators on the formation of radicals in the reaction mixtures of rat liver microsomes with ADP, Fe and NADPH. J. Clin. Biochem. Nutr.49, 207–215 (2011). ArticleCASPubMedPubMed Central Google Scholar
Ceresoli-Borroni, G., Guidetti, P., Amori, L., Pellicciari, R. & Schwarcz, R. Perinatal kynurenine 3-hydroxylase inhibition in rodents: pathophysiological implications. J. Neurosci. Res.85, 845–854 (2007). ArticleCASPubMed Google Scholar
Oxenkrug, G. F. Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders. J. Neural Transm.118, 75–85 (2011). ArticleCASPubMed Google Scholar
Thomas, S. R. & Stocker, R. Redox reactions related to indoleamine 2,3-dioxygenase and tryptophan metabolism along the kynurenine pathway. Redox Rep.4, 199–220 (1999). ArticleCASPubMed Google Scholar
Ball, H. J., Yuasa, H. J., Austin, C. J., Weiser, S. & Hunt, N. H. Indoleamine 2,3-dioxygenase-2; a new enzyme in the kynurenine pathway. Int. J. Biochem. Cell Biol.41, 467–471 (2009). ArticleCASPubMed Google Scholar
Ren, S. & Correia, M. A. Heme: a regulator of rat hepatic tryptophan 2,3-dioxygenase? Arch. Biochem. Biophys.377, 195–203 (2000). ArticleCASPubMed Google Scholar
Han, Q., Cai, T., Tagle, D. A. & Li, J. Structure, expression, and function of kynurenine aminotransferases in human and rodent brains. Cell. Mol. Life Sci.67, 353–368 (2010). ArticleCASPubMed Google Scholar
Guidetti, P., Amori, L., Sapko, M. T., Okuno, E. & Schwarcz, R. Mitochondrial aspartate aminotransferase: a third kynurenate-producing enzyme in the mammalian brain. J. Neurochem.102, 103–111 (2007). ArticleCASPubMed Google Scholar
Kawai, J., Okuno, E. & Kido, R. Organ distribution of rat kynureninase and changes of its activity during development. Enzyme39, 181–189 (1988). ArticleCASPubMed Google Scholar
Foster, A. C., White, R. J. & Schwarcz, R. Synthesis of quinolinic acid by 3-hydroxyanthranilic acid oxygenase in rat brain tissue in vitro. J. Neurochem.47, 23–30 (1986). ArticleCASPubMed Google Scholar
Stachowski, E. & Schwarcz, R. Regulation of quinolinic acid neosynthesis in mouse, rat, and human brain by iron and iron chelation in vitro. J. Neural Transm.119, 123–131 (2012). ArticleCASPubMed Google Scholar
Pucci, L., Perozzi, S., Cimadamore, F., Orsomando, G. & Raffaelli, N. Tissue expression and biochemical characterization of human 2-amino-carboxymuconate 6-semialdehyde decarboxylase, a key enzyme in tryptophan catabolism. FEBS J.274, 827–840 (2007). ArticleCASPubMed Google Scholar
Foster, A. C., Zinkand, W. C. & Schwarcz, R. Quinolinic acid phosphoribosyltransferase in rat brain. J. Neurochem.44, 446–454 (1985). ArticleCASPubMed Google Scholar
Braidy, N., Guillemin, G. J. & Grant, R. Effects of kynurenine pathway inhibition on NAD metabolism and cell viability in human primary astrocytes and neurons. Int. J. Tryptophan Res.4, 29–37 (2011). ArticleCASPubMedPubMed Central Google Scholar
Bellac, C. L., Coimbra, R. S., Christen, S. & Leib, S. L. Inhibition of the kynurenine-NAD+ pathway leads to energy failure and exacerbates apoptosis in pneumococcal meningitis. J. Neuropathol. Exp. Neurol.69, 1096–1104 (2010). ArticleCASPubMed Google Scholar
Guillemin, G. J. et al. Characterisation of kynurenine pathway metabolism in human astrocytes and implications in neuropathogenesis. Redox Rep.5, 108–111 (2000). ArticleCASPubMed Google Scholar
Guidetti, P., Hoffman, G. E., Melendez-Ferro, M., Albuquerque, E. X. & Schwarcz, R. Astrocytic localization of kynurenine aminotransferase II in the rat brain visualized by immunocytochemistry. Glia55, 78–92 (2007). ArticlePubMed Google Scholar
Liao, M. et al. Impaired dexamethasone-mediated induction of tryptophan 2,3-dioxygenase in heme-deficient rat hepatocytes: translational control by a hepatic eIF2α kinase, the heme-regulated inhibitor. J. Pharmacol. Exp. Ther.323, 979–989 (2007). ArticleCASPubMed Google Scholar
Connor, T. J., Starr, N., O'Sullivan, J. B. & Harkin, A. Induction of indolamine 2,3-dioxygenase and kynurenine 3-monooxygenase in rat brain following a systemic inflammatory challenge: a role for IFN-γ? Neurosci. Lett.441, 29–34 (2008). ArticleCASPubMed Google Scholar
Cady, S. G. & Sono, M. 1-Methyl-DL-tryptophan, beta-(3-benzofuranyl)-DL-alanine (the oxygen analog of tryptophan), and beta-[3-benzo(b)thienyl]-DL-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase. Arch. Biochem. Biophys.291, 326–333 (1991). ArticleCASPubMed Google Scholar
Amori, L., Guidetti, P., Pellicciari, R., Kajii, Y. & Schwarcz, R. On the relationship between the two branches of the kynurenine pathway in the rat brain in vivo. J. Neurochem.109, 316–325 (2009). ArticleCASPubMedPubMed Central Google Scholar
Walsh, H. A., Leslie, P. L., O'Shea, K. C. & Botting, N. P. 2-Amino-4-[3′-hydroxyphenyl]-4-hydroxybutanoic acid; a potent inhibitor of rat and recombinant human kynureninase. Bioorg. Med. Chem. Lett.12, 361–363 (2002). ArticleCASPubMed Google Scholar
Luthman, J. Anticonvulsant effects of the 3-hydroxyanthranilic acid dioxygenase inhibitor NCR-631. Amino Acids19, 325–334 (2000). ArticleCASPubMed Google Scholar