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Assessing and Modulating Kynurenine Pathway Dynamics in Huntington’s Disease: Focus on Kynurenine 3-Monooxygenase

  • Korrapati V. Sathyasaikumar
  • Carlo Breda
  • Robert Schwarcz
  • Flaviano Giorgini
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1780)

Abstract

The link between disturbances in kynurenine pathway (KP) metabolism and Huntington’s disease (HD) pathogenesis has been explored for a number of years. Several novel genetic and pharmacological tools have recently been developed to modulate key regulatory steps in the KP such as the reaction catalyzed by the enzyme kynurenine 3-monooxygenase (KMO). This insight has offered new options for exploring the mechanistic link between this metabolic pathway and HD, and provided novel opportunities for the development of candidate drug-like compounds. Here, we present an overview of the field, focusing on some novel approaches for interrogating the pathway experimentally.

Keywords

Huntington’s disease Kynurenine pathway Kynurenine 3-monooxygenase (KMO) 

Notes

Acknowledgements

We are grateful to Louis Fernandes (Harvard Brain Tissue Resource Center, Boston, MA, USA) for providing human brain tissue for this study. We also thank Erin Stachowski for excellent technical assistance with the measurement of 3-HK levels and KP enzyme activities in human brain tissues. F.G. thanks the Medical Research Council for funding (MR/N00373X/1).

References

  1. 1.
    Schwarcz R, Whetsell WO Jr, Mangano RM (1983) Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science 219:316–318PubMedCrossRefGoogle Scholar
  2. 2.
    Stone TW, Perkins MN (1981) Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharmacol 72:411–412PubMedCrossRefGoogle Scholar
  3. 3.
    Santamaría A, Flores-Escartin A, Martinez JC et al (2003) Copper blocks quinolinic acid neurotoxicity in rats: contribution of antioxidant systems. Free Radic Biol Med 35:418–427PubMedCrossRefGoogle Scholar
  4. 4.
    Beal MF, Kowall NW, Ellison DW et al (1986) Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature 321:168–171PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Ishii T, Iwahashi H, Sugata R et al (1992) Formation of hydroxanthommatin-derived radical in the oxidation of 3-hydroxykynurenine. Arch Biochem Biophys 294:616–622PubMedCrossRefGoogle Scholar
  6. 6.
    Hiraku Y, Inoue S, Oikawa S et al (1995) Metal-mediated oxidative damage to cellular and isolated DNA by certain tryptophan metabolites. Carcinogenesis 16:349–356PubMedCrossRefGoogle Scholar
  7. 7.
    Eastman CL, Guilarte TR (1989) Cytotoxicity of 3-hydroxykynurenine in a neuronal hybrid cell line. Brain Res 495:225–231PubMedCrossRefGoogle Scholar
  8. 8.
    Eastman CL, Guilarte TR (1990) The role of hydrogen peroxide in the in vitro cytotoxicity of 3-hydroxykynurenine. Neurochem Res 15:1101–1107PubMedCrossRefGoogle Scholar
  9. 9.
    Okuda S, Nishiyama N, Saito H et al (1996) Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine. Proc Natl Acad Sci U S A 93:12553–12558PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Guidetti P, Schwarcz R (1999) 3-Hydroxykynurenine potentiates quinolinate but not NMDA toxicity in the rat striatum. Eur J Neurosci 11:3857–3863PubMedCrossRefGoogle Scholar
  11. 11.
    Maddison DC, Giorgini F (2015) The kynurenine pathway and neurodegenerative disease. Semin Cell Dev Biol 40:134–141PubMedCrossRefGoogle Scholar
  12. 12.
    Perkins MN, Stone TW (1982) An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res 247:184–187PubMedCrossRefGoogle Scholar
  13. 13.
    Parsons CG, Danysz W, Quack G et al (1997) Novel systemically active antagonists of the glycine site of the N-methyl-d-aspartate receptor: electrophysiological, biochemical and behavioral characterization. J Pharmacol Exp Ther 283:1264–1275PubMedGoogle Scholar
  14. 14.
    Hilmas C, Pereira EF, Alkondon M et al (2001) The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neurosci 21:7463–7473PubMedCrossRefGoogle Scholar
  15. 15.
    Lugo-Huitrón R, Blanco-Ayala T, Ugalde-Muniz P et al (2011) On the antioxidant properties of kynurenic acid: free radical scavenging activity and inhibition of oxidative stress. Neurotoxicol Teratol 33:538–547PubMedCrossRefGoogle Scholar
  16. 16.
    Moroni F, Cozzi A, Sili M et al (2012) Kynurenic acid: a metabolite with multiple actions and multiple targets in brain and periphery. J Neural Transm 119:133–139PubMedCrossRefGoogle Scholar
  17. 17.
    Fazio F, Lionetto L, Curto M et al (2017) Cinnabarinic acid and xanthurenic acid: two kynurenine metabolites that interact with metabotropic glutamate receptors. Neuropharmacology 112:365–372PubMedCrossRefGoogle Scholar
  18. 18.
    Stone TW, Stoy N, Darlington LG (2013) An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol Sci 34:136–143PubMedCrossRefGoogle Scholar
  19. 19.
    Bohar Z, Toldi J, Fülöp F et al (2015) Changing the face of kynurenines and neurotoxicity: therapeutic considerations. Int J Mol Sci 16:9772–9793PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Pearson SJ, Reynolds GP (1992) Increased brain concentrations of a neurotoxin, 3-hydroxykynurenine, in Huntington’s disease. Neurosci Lett 144:199–201PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Guidetti P, Luthi-Carter RE, Augood SJ et al (2004) Neostriatal and cortical quinolinate levels are increased in early grade Huntington’s disease. Neurobiol Dis 17:455–461PubMedCrossRefGoogle Scholar
  22. 22.
    Forrest CM, Mackay GM, Stoy N et al (2010) Blood levels of kynurenines, interleukin-23 and soluble human leucocyte antigen-G at different stages of Huntington’s disease. J Neurochem 112:112–122PubMedCrossRefGoogle Scholar
  23. 23.
    Stoy N, Mackay GM, Forrest CM et al (2005) Tryptophan metabolism and oxidative stress in patients with Huntington’s disease. J Neurochem 93:611–623PubMedCrossRefGoogle Scholar
  24. 24.
    Guidetti P, Reddy PH, Tagle DA et al (2000) Early kynurenergic impairment in Huntington’s disease and in a transgenic animal model. Neurosci Lett 283:233–235PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Guidetti P, Bates GP, Graham RK et al (2006) Elevated brain 3-hydroxykynurenine and quinolinate levels in Huntington disease mice. Neurobiol Dis 23:190–197PubMedCrossRefGoogle Scholar
  26. 26.
    Sathyasaikumar KV, Stachowski EK, Amori L et al (2010) Dysfunctional kynurenine pathway metabolism in the R6/2 mouse model of Huntington’s disease. J Neurochem 113:1416–1425PubMedPubMedCentralGoogle Scholar
  27. 27.
    Giorgini F, Möller T, Kwan W et al (2008) Histone deacetylase inhibition modulates kynurenine pathway activation in yeast, microglia, and mice expressing a mutant huntingtin fragment. J Biol Chem 283:7390–7400PubMedCrossRefGoogle Scholar
  28. 28.
    Giorgini F, Guidetti P, Nguyen Q et al (2005) A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Nat Genet 37:526–531PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Campesan S, Green EW, Breda C et al (2011) The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington’s disease. Curr Biol 21:961–966PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Larkin PB, Sathyasaikumar KV, Notarangelo FM et al (2016) Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice. Biochim Biophys Acta 1860:2345–2354PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Breda C, Sathyasaikumar KV, Sograte Idrissi S et al (2016) Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites. Proc Natl Acad Sci U S A 113:5435–5440PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    van der Goot AT, Zhu W, Vazquez-Manrique RP et al (2012) Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation. Proc Natl Acad Sci U S A 109:14912–14917PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    van der Goot AT, Nollen EA (2013) Tryptophan metabolism: entering the field of aging and age-related pathologies. Trends Mol Med 19:336–344PubMedCrossRefGoogle Scholar
  34. 34.
    Mazarei G, Leavitt BR (2015) Indoleamine 2,3 dioxygenase as a potential therapeutic target in Huntington’s disease. J Huntingtons Dis 4:109–118PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Mazarei G, Budac DP, Lu G et al (2013) Age-dependent alterations of the kynurenine pathway in the YAC128 mouse model of Huntington disease. J Neurochem 127:852–867PubMedCrossRefGoogle Scholar
  36. 36.
    Austin CJ, Rendina LM (2015) Targeting key dioxygenases in tryptophan-kynurenine metabolism for immunomodulation and cancer chemotherapy. Drug Discov Today 20:609–617PubMedCrossRefGoogle Scholar
  37. 37.
    Green EW, Campesan S, Breda C et al (2012) Drosophila eye color mutants as therapeutic tools for Huntington disease. Fly (Austin) 6:117–120CrossRefGoogle Scholar
  38. 38.
    Zwilling D, Huang SY, Sathyasaikumar KV et al (2011) Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell 145:863–874PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Beaumont V, Mrzljak L, Dijkman U et al (2016) The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington’s disease. Exp Neurol 282:99–118PubMedCrossRefGoogle Scholar
  40. 40.
    Sathyasaikumar KV, Stachowski EK, Wonodi I et al (2011) Impaired kynurenine pathway metabolism in the prefrontal cortex of individuals with schizophrenia. Schizophr Bull 37:1147–1156PubMedCrossRefGoogle Scholar
  41. 41.
    Jauch D, Urbanska EM, Guidetti P et al (1995) Dysfunction of brain kynurenic acid metabolism in Huntington’s disease: focus on kynurenine aminotransferases. J Neurol Sci 130:39–47PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Pearson SJ, Meldrum A, Reynolds GP (1995) An investigation of the activities of 3-hydroxykynureninase and kynurenine aminotransferase in the brain in Huntington’s disease. J Neural Transm Gen Sect 102:67–73PubMedCrossRefGoogle Scholar
  43. 43.
    Schwarcz R, Okuno E, White RJ et al (1988) 3-Hydroxyanthranilate oxygenase activity is increased in the brains of Huntington disease victims. Proc Natl Acad Sci U S A 85:4079–4081PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Foster AC, Whetsell WO Jr, Bird ED et al (1985) Quinolinic acid phosphoribosyltransferase in human and rat brain: activity in Huntington's disease and in quinolinate-lesioned rat striatum. Brain Res 336:207–214PubMedCrossRefGoogle Scholar
  45. 45.
    Maragakis NJ, Rothstein JD (2006) Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2:679–689PubMedCrossRefGoogle Scholar
  46. 46.
    Politis M, Pavese N, Tai YF et al (2011) Microglial activation in regions related to cognitive function predicts disease onset in Huntington’s disease: a multimodal imaging study. Hum Brain Mapp 32:258–270PubMedCrossRefGoogle Scholar
  47. 47.
    Verkhratsky A, Parpura V, Pekna M et al (2014) Glia in the pathogenesis of neurodegenerative diseases. Biochem Soc Trans 42:1291–1301PubMedCrossRefGoogle Scholar
  48. 48.
    Bouvier DS, Murai KK (2015) Synergistic actions of microglia and astrocytes in the progression of Alzheimer’s disease. J Alzheimers Dis 45:1001–1014PubMedCrossRefGoogle Scholar
  49. 49.
    Guidetti P, Eastman CL, Schwarcz R (1995) Metabolism of [5-3H]kynurenine in the rat brain in vivo: evidence for the existence of a functional kynurenine pathway. J Neurochem 65:2621–2632CrossRefGoogle Scholar
  50. 50.
    Okamoto H, Hayaishi O (1969) Solubilization and partial purification of kynurenine hydroxylase from mitochondrial outer membrane and its electron donors. Arch Biochem Biophys 131:603–608PubMedCrossRefGoogle Scholar
  51. 51.
    Thevandavakkam MA, Schwarcz R, Muchowski PJ et al (2011) Targeting kynurenine 3-monooxygenase (KMO): implications for therapy in Huntington’s disease. CNS Neurol Disord Drug Targets 9:791–800CrossRefGoogle Scholar
  52. 52.
    Amaral M, Levy C, Heyes DJ et al (2013) Structural basis of kynurenine 3-monooxygenase inhibition. Nature 496:382–385PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Giorgini F (2008) The kynurenine pathway and microglia: implications for pathology and therapy in Huntington’s disease. In: Outeiro T (ed) Protein Misfolding in Biology and Disease. Transworld Research Network, Kerala, India, pp 231–255Google Scholar
  54. 54.
    Sathyasaikumar KV, Severson P, West BL et al (2016) Elimination of microglia in adult mouse forebrain does not alter kynurenine 3-monooxygenase activity. Soc Neurosci Abstr 41:37:19Google Scholar
  55. 55.
    Heyes MP, Saito K, Markey SP (1992) Human macrophages convert l-tryptophan into the neurotoxin quinolinic acid. Biochem J 283:633–635PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    De Castro FT, Brown RR, Price JM (1957) The intermediary metabolism of tryptophan by cat and rat tissue preparations. J Biol Chem 28:777–784Google Scholar
  57. 57.
    Smith JR, Jamie JF, Guillemin GJ (2016) Kynurenine-3-monooxygenase: a review of structure, mechanism, and inhibitors. Drug Discov Today 21:315–324PubMedCrossRefGoogle Scholar
  58. 58.
    Pellicciari R, Natalini B, Costantino G et al (1994) Modulation of the kynurenine pathway in search for new neuroprotective agents. Synthesis and preliminary evaluation of (m-nitrobenzoyl)alanine, a potent inhibitor of kynurenine-3-hydroxylase. J Med Chem 37:647–655PubMedCrossRefGoogle Scholar
  59. 59.
    Cozzi A, Carpenedo R, Moroni F (1999) Kynurenine hydroxylase inhibitors reduce ischemic brain damage: studies with (m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]-benzenesulfonamide (Ro 61-8048) in models of focal or global brain ischemia. J Cereb Blood Flow Metab 19:771–777PubMedCrossRefGoogle Scholar
  60. 60.
    Speciale C, Wu HQ, Cini M et al (1996) (R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats. Eur J Pharmacol 315:263–267PubMedCrossRefGoogle Scholar
  61. 61.
    Röver S, Cesura AM, Huguenin P et al (1997) Synthesis and biochemical evaluation of N-(4-phenylthiazol-2-yl)benzenesulfonamides as high-affinity inhibitors of kynurenine 3-hydroxylase. J Med Chem 40:4378–4385PubMedCrossRefGoogle Scholar
  62. 62.
    Schwarcz R, Bruno JP, Muchowski PJ et al (2012) Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci 13:465–477PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Beconi MG, Yates D, Lyons K et al (2012) Metabolism and pharmacokinetics of JM6 in mice: JM6 is not a prodrug for Ro-61-8048. Drug Metab Dispos 40:2297–2306PubMedCrossRefGoogle Scholar
  64. 64.
    Vengeliene V, Cannella N, Takahashi T et al (2016) Metabolic shift of the kynurenine pathway impairs alcohol and cocaine seeking and relapse. Psychopharmacology 233:3449–3459PubMedCrossRefGoogle Scholar
  65. 65.
    Rojewska E, Piotrowska A, Makuch W et al (2016) Pharmacological kynurenine 3-monooxygenase enzyme inhibition significantly reduces neuropathic pain in a rat model. Neuropharmacology 102:80–91PubMedCrossRefGoogle Scholar
  66. 66.
    Amori L, Guidetti P, Pellicciari R et al (2009) On the relationship between the two branches of the kynurenine pathway in the rat brainin vivo. J Neurochem 109:316–325PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Ceresoli-Borroni G, Guidetti P, Amori L et al (2007) Perinatal kynurenine 3-hydroxylase inhibition in rodents: pathophysiological implications. J Neurosci Res 85:845–854PubMedCrossRefGoogle Scholar
  68. 68.
    Sapko MT, Guidetti P, Yu P et al (2006) Endogenous kynurenate controls the vulnerability of striatal neurons to quinolinate: implications for Huntington’s disease. Exp Neurol 197:31–40PubMedCrossRefGoogle Scholar
  69. 69.
    Toledo-Sherman LM, Prime ME, Mrzljak L et al (2015) Development of a series of aryl pyrimidine kynurenine monooxygenase inhibitors as potential therapeutic agents for the treatment of Huntington’s disease. J Med Chem 58:1159–1183PubMedCrossRefGoogle Scholar
  70. 70.
    Mole DJ, Webster SP, Uings I et al (2016) Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis. Nat Med 22:202–209PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Bouleau S, Tricoire H (2015) Drosophila models of Alzheimer’s disease: advances, limits, and perspectives. J Alzheimers Dis 45:1015–1038PubMedCrossRefGoogle Scholar
  72. 72.
    Morgan TH (1910) Sex limited inheritance in Drosophila. Science 32:120–122PubMedCrossRefGoogle Scholar
  73. 73.
    Tearle R (1991) Tissue specific effects of ommochrome pathway mutations in Drosophila melanogaster. Genet Res 57:257–266PubMedCrossRefGoogle Scholar
  74. 74.
    Roberts JE (2001) Ocular phototoxicity. J Photochem Photobiol B 64:136–143PubMedCrossRefGoogle Scholar
  75. 75.
    Savvateeva EV, Popov AV, Kamyshev NG et al (1999) Age-dependent changes in memory and mushroom bodies in the Drosophila mutant vermilion deficient in the kynurenine pathway of tryptophan metabolism. Ross Fiziol Zh Im I M Sechenova 85:167–183PubMedGoogle Scholar
  76. 76.
    Oxenkrug GF (2010) The extended life span of Drosophila melanogaster eye-color (white and vermilion) mutants with impaired formation of kynurenine. J Neural Transm 117:23–26PubMedCrossRefGoogle Scholar
  77. 77.
    Oxenkrug GF, Navrotskaya V, Voroboyva L et al (2011) Extension of life span of Drosophila melanogaster by the inhibitors of tryptophan-kynurenine metabolism. Fly (Austin) 5:307–309CrossRefGoogle Scholar
  78. 78.
    Brinzer RA, Henderson L, Marchiondo AA et al (2015) Metabolomic profiling of permethrin-treated Drosophila melanogaster identifies a role for tryptophan catabolism in insecticide survival. Insect Biochem Mol Biol 67:74–86PubMedCrossRefGoogle Scholar
  79. 79.
    Navrotskaya V, Oxenkrug G, Vorobyova L et al (2015) Attenuation of high sucrose diet-induced insulin resistance in tryptophan 2,3-dioxygenase deficient Drosophila melanogaster vermilion mutants. Integr Obes Diabetes 1:93–95PubMedPubMedCentralGoogle Scholar
  80. 80.
    Savvateeva E, Popov A, Kamyshev N et al (2000) Age-dependent memory loss, synaptic pathology and altered brain plasticity in the Drosophila mutant cardinal accumulating 3-hydroxykynurenine. J Neural Transm 107:581–601PubMedCrossRefGoogle Scholar
  81. 81.
    Popov AV, Peresleni AI, Savvateeva-Popova EV et al (2008) Effect of mutation-induced excess brain concentration of intermediates of the kynurenine pathway of tryptophan metabolism on stress resistance and courtship behavior and communicative sound production in male Drosophila melanogaster. Genetika 44:1216–1226PubMedGoogle Scholar
  82. 82.
    Savvateeva-Popova EV, Popov AV, Heinemann T et al (2003) Drosophila mutants of the kynurenine pathway as a model for ageing studies. Adv Exp Med Biol 527:713–722PubMedCrossRefGoogle Scholar
  83. 83.
    Linzen B (1974) Tryptophan – ommochrome pathway in insects. Adv Insect Physiol 10:117–246CrossRefGoogle Scholar
  84. 84.
    Dietzl G, Chen D, Schnorrer F et al (2007) A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448:151–156PubMedCrossRefGoogle Scholar
  85. 85.
    Brenner S (1974) The genetics of Caenorhabditis elegans. Genetics 77:71–94PubMedPubMedCentralGoogle Scholar
  86. 86.
    White JG, Southgate E, Thomson JN et al (1986) The structure of the nervous system of the nematode Caenorhabditis elegans. Philos Trans R Soc Lond Ser B Biol Sci 314:1–340CrossRefGoogle Scholar
  87. 87.
    Culetto E, Sattelle DB (2000) A role for Caenorhabditis elegans in understanding the function and interactions of human disease genes. Hum Mol Genet 9:869–877PubMedCrossRefGoogle Scholar
  88. 88.
    Fire A, Xu S, Montgomery MK et al (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811PubMedCrossRefGoogle Scholar
  89. 89.
    Coburn C, Gems D (2013) The mysterious case of the C. elegans gut granule: death fluorescence, anthranilic acid and the kynurenine pathway. Front Genet 4:151PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Babu P (1974) Biochemical genetics of Caenorhabditis elegans. Mol Gen Genet 135:39–44CrossRefGoogle Scholar
  91. 91.
    Bhat SG, Babu P (1980) Mutagen sensitivity of kynureninase mutants of the nematode Caenorhabditis elegans. Mol Gen Genet 180:635–638PubMedCrossRefGoogle Scholar
  92. 92.
    Justice MJ, Siracusa LD, Stewart AF (2011) Technical approaches for mouse models of human disease. Dis Model Mech 4:305–310PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Giorgini F, Huang SY, Sathyasaikumar KV et al (2013) Targeted deletion of kynurenine 3-monooxygenase in mice: a new tool for studying kynurenine pathway metabolism in periphery and brain. J Biol Chem 288:36554–36566PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Terakata M, Fukuwatari T, Sano M et al (2012) Establishment of true niacin deficiency in quinolinic acid phosphoribosyltransferase knockout mice. J Nutr 142:2148–2153PubMedCrossRefGoogle Scholar
  95. 95.
    Kanai M, Funakoshi H, Takahashi H et al (2009) Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice. Mol Brain 2:8PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Baban B, Chandler P, McCool D et al (2004) Indoleamine 2,3-dioxygenase expression is restricted to fetal trophoblast giant cells during murine gestation and is maternal genome specific. J Reprod Immunol 61:67–77PubMedCrossRefGoogle Scholar
  97. 97.
    Forrest CM, McNair K, Pisar M et al (2015) Altered hippocampal plasticity by prenatal kynurenine administration, kynurenine 3-monooxygenase (KMO) deletion or galantamine. Neuroscience 310:91–105PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Erhardt S, Pocivavsek A, Repici M et al (2017) Adaptive and behavioral changes in kynurenine 3-monooxygenase knockout mice: relevance to psychotic disorders. Biol Psychiatry 82:756–765PubMedCrossRefGoogle Scholar
  99. 99.
    Skarnes WC, Rosen B, West AP et al (2011) A conditional knockout resource for the genome-wide study of mouse gene function. Nature 474:337–342PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Heisler JM, O’Connor JC (2015) Indoleamine 2,3-dioxygenase-dependent neurotoxic kynurenine metabolism mediates inflammation-induced deficit in recognition memory. Brain Behav Immun 50:115–124PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Parrott JM, Redus L, Santana-Coelho D et al (2016) Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation. Transl Psychiatry 6:e918PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Tashiro T, Murakami Y, Mouri A et al (2017) Kynurenine 3-monooxygenase is implicated in antidepressants-responsive depressive-like behaviors and monoaminergic dysfunctions. Behav Brain Res 317:279–285PubMedCrossRefGoogle Scholar
  103. 103.
    Korstanje R, Deutsch K, Bolanos-Palmieri P et al (2016) Loss of kynurenine 3-mono-oxygenase causes proteinuria. J Am Soc Nephrol 27:3271–3277PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Kubo H, Hoshi M, Mouri A et al (2017) Absence of kynurenine 3-monooxygenase reduces mortality of acute viral myocarditis in mice. Immunol Lett 181:94–100PubMedCrossRefGoogle Scholar
  105. 105.
    Andre R, Carty L, Tabrizi SJ (2016) Disruption of immune cell function by mutant huntingtin in Huntington’s disease pathogenesis. Curr Opin Pharmacol 26:33–38PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Korrapati V. Sathyasaikumar
    • 1
  • Carlo Breda
    • 2
  • Robert Schwarcz
    • 1
  • Flaviano Giorgini
    • 2
  1. 1.Maryland Psychiatric Research Center, Department of PsychiatryUniversity of Maryland School of MedicineBaltimoreUSA
  2. 2.Department of Genetics and Genome BiologyUniversity of LeicesterLeicesterUK

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