316
Views
1
CrossRef citations to date
0
Altmetric
Review

Rollercoaster ride of kynurenines: steering the wheel towards neuroprotection in Alzheimer’s disease

, , &
Pages 849-867 | Received 22 Jun 2018, Accepted 13 Sep 2018, Published online: 25 Sep 2018

References

  • Hebert LE, Weuve J, Scherr PA, et al. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology. 2013 May 7;80(19):1778–1783. PubMed PMID: 23390181; PubMed Central PMCID: PMC3719424.
  • Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet. 2005 Dec 17;366(9503):2112–2117. PubMed PMID: 16360788; PubMed Central PMCID: PMC2850264.
  • Prince MJ. World Alzheimer Report 2015: the global impact of dementia: an analysis of prevalence, incidence, cost and trends. Alzheimer’s Disease International; 2015.
  • Perl DP. Neuropathology of Alzheimer’s disease. The Mount Sinai J Med. New York. 2010 Jan-Feb;77(1):32–42. . PubMed PMID: 20101720; PubMed Central PMCID: PMC2918894.
  • Zolezzi JM, Bastias-Candia S, Santos MJ, et al. Alzheimer’s disease: relevant molecular and physiopathological events affecting amyloid-beta brain balance and the putative role of PPARs. Front Aging Neurosci. 2014;6:176. . PubMed PMID: 25120477; PubMed Central PMCID: PMC4112937.
  • Robakis NK. Molecular neuropathology of Alzheimer dementia and therapeutic approaches. Adv Exp Med Biol. 2015;822:1. . PubMed PMID: 25416969.
  • Lapin IP. Stimulant and convulsive effects of kynurenines injected into brain ventricles in mice. J Neural Transm. 1978;42(1):37–43. PubMed PMID: 641543.
  • Stone TW, Perkins MN. Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharmacol. 1981 Jul 10;72(4):411–412. PubMed PMID: 6268428.
  • Foster AC, Vezzani A, French ED, et al. KYNA blocks neurotoxicity and seizures induced in rats by the related brain metabolite quinolinic acid. Neurosci Lett. 1984 Aug 10;48(3):273–278. PubMed PMID: 6237279.
  • Perkins MN, Stone TW. An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res. 1982 Sep 9;247(1):184–187. PubMed PMID: 6215086.
  • Perez-De La Cruz V, Konigsberg M, Santamaria A. KP and disease: an overview. CNS Neurol Disord Drug Targets. 2007 Dec;6(6):398–410. PubMed PMID: 18220779.
  • Gulaj E, Pawlak K, Bien B, et al. Kynurenine and its metabolites in Alzheimer’s disease patients. Adv Med Sci. 2010;55(2):204–211. . PubMed PMID: 20639188.
  • Bonda DJ, Mailankot M, Stone JG, et al. Indoleamine 2,3-dioxygenase and 3-hydroxykynurenine modifications are found in the neuropathology of Alzheimer’s disease. Redox Rep: Commun Free Radical Res. 2010;15(4):161–168. . PubMed PMID: 20663292; PubMed Central PMCID: PMC2956440.
  • Guillemin GJ, Brew B, Noonan C, et al. Indoleamine 2, 3 dioxygenase and QUIN immunoreactivity in Alzheimer’s disease hippocampus. Neuropathol Appl Neurobiol. 2005;31(4):395–404.
  • Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discovery. 2011 Aug 19;10(9):698–712. . PubMed PMID: 21852788.
  • Hamley IW. The amyloid beta peptide: a chemist’s perspective. Role in Alzheimer’s and fibrillization. Chem Rev. 2012 Oct 10;112(10):5147–5192. . PubMed PMID: 22813427.
  • Olsson F, Schmidt S, Althoff V, et al. Characterization of intermediate steps in amyloid beta (Abeta) production under near-native conditions. J Biol Chem. 2014 Jan 17;289(3):1540–1550. PubMed PMID: 24225948; PubMed Central PMCID: PMC3894335.
  • Yan R, Vassar R. Targeting the beta secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol. 2014 Mar;13(3):319–329. . PubMed PMID: 24556009; PubMed Central PMCID: PMC4086426.
  • Goate A, Chartier-Harlin MC, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 1991 Feb 21;349(6311):704–706. PubMed PMID: 1671712.
  • Sherrington R, Rogaev EI, Liang Y, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature. 1995 Jun 29;375(6534):754–760. PubMed PMID: 7596406.
  • Zolezzi JM, Inestrosa NC. Peroxisome proliferator-activated receptors and Alzheimer’s disease: hitting the blood-brain barrier. Mol Neurobiol. 2013 Dec;48(3):438–451. . PubMed PMID: 23494748.
  • Li J, Kanekiyo T, Shinohara M, et al. Differential regulation of amyloid-beta endocytic trafficking and lysosomal degradation by apolipoprotein E isoforms. J Biol Chem. 2012 Dec 28;287(53):44593–44601. PubMed PMID: 23132858; PubMed Central PMCID: PMC3531774.
  • Deane R, Sagare A, Zlokovic BV. The role of the cell surface LRP and soluble LRP in blood-brain barrier Abeta clearance in Alzheimer’s disease. Curr Pharm Des. 2008;14(16):1601–1605. PubMed PMID: 18673201; PubMed Central PMCID: PMC2895311.
  • Nilsson P, Saido TC. Dual roles for autophagy: degradation and secretion of Alzheimer’s disease Abeta peptide. BioEssays: News Rev Mol Cel Dev Biol. 2014 Jun;36(6):570–578. . PubMed PMID: 24711225; PubMed Central PMCID: PMC4316186.
  • Zhao J, O’Connor T, Vassar R. The contribution of activated astrocytes to Abeta production: implications for Alzheimer’s disease pathogenesis. J Neuroinflammation. 2011 Nov 2;8:150. . PubMed PMID: 22047170; PubMed Central PMCID: PMC3216000.
  • Mizuno T. The biphasic role of microglia in Alzheimer’s disease. Int j Alzheimer’s dis. 2012;2012:737846. . PubMed PMID: 22655214; PubMed Central PMCID: PMC3357927.
  • Otth C, Concha II, Arendt T, et al. AbetaPP induces cdk5-dependent tau hyperphosphorylation in transgenic mice Tg2576. J Alzheimer’s disease: JAD. 2002 Oct;4(5):417–430. PubMed PMID: 12446973.
  • Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010 Jan 28;362(4):329–344. . PubMed PMID: 20107219.
  • Bartus RT, Dean RL 3rd, Beer B, et al. The cholinergic hypothesis of geriatric memory dysfunction. Science. 1982 Jul 30;217(4558):408–414. PubMed PMID: 7046051.
  • Mesulam MM, Mufson EJ, Wainer BH, et al. Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience. 1983 Dec;10(4):1185–1201. PubMed PMID: 6320048.
  • Shigematsu K, McGeer PL, McGeer EG. Localization of amyloid precursor protein in selective postsynaptic densities of rat cortical neurons. Brain Res. 1992 Oct 2;592(1–2):353–357. PubMed PMID: 1280522.
  • Chessell IP, Francis PT, Pangalos MN, et al. Localisation of muscarinic (m1) and other neurotransmitter receptors on corticofugal-projecting pyramidal neurones. Brain Res. 1993 Dec 31;632(1–2):86–94. PubMed PMID: 8149248.
  • Caccamo A, Oddo S, Billings LM, et al. M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron. 2006 Mar 2;49(5):671–682. . PubMed PMID: 16504943.
  • Buckingham SD, Jones AK, Brown LA, et al. Nicotinic acetylcholine receptor signalling: roles in Alzheimer’s disease and amyloid neuroprotection. Pharmacol Rev. 2009 Mar;61(1):39–61. PubMed PMID: 19293145; PubMed Central PMCID: PMC2830120.
  • Davies P, Maloney A. Selective loss of central cholinergic neurons in Alzheimer’s disease. The Lancet. 1976;308(8000):1403.
  • Perry E. Acetylcholine and Alzheimer’s disease. Br J Psychiatry. 1988;152(6):737–740.
  • Lehéricy S, Éc H, Cervera‐Piérot P, et al. Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer’s disease. J Comp Neurol. 1993;330(1):15–31.
  • Rylett R, Ball M, Colhoun E. Evidence for high affinity choline transport in synaptosomes prepared from hippocampus and neocortex of patients with Alzheimer’s disease. Brain Res. 1983;289(1–2):169–175.
  • Nilsson L, Nordberg A, Hardy J, et al. Physostigmine restores 3 H-acetylcholine efflux from Alzheimer brain slices to normal level. J Neural Transm. 1986;67(3–4):275–285.
  • Whitehouse PJ, Price DL, Struble RG, et al. Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science. 1982;215(4537):1237–1239.
  • Busciglio J, Gabuzda DH, Matsudaira P, et al. Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):2092–2096. PubMed PMID: 8446635; PubMed Central PMCID: PMC46027.
  • Buxbaum JD, Koo EH, Greengard P. Protein phosphorylation inhibits production of Alzheimer amyloid beta/A4 peptide. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9195–9198. PubMed PMID: 8415676; PubMed Central PMCID: PMC47529.
  • Gabuzda D, Busciglio J, Yankner BA. Inhibition of beta-amyloid production by activation of protein kinase C. J Neurochem. 1993 Dec;61(6):2326–2329. PubMed PMID: 8245986.
  • Wolf BA, Wertkin AM, Jolly YC, et al. Muscarinic regulation of Alzheimer’s disease amyloid precursor protein secretion and amyloid beta-protein production in human neuronal NT2N cells. J Biol Chem. 1995 Mar 3;270(9):4916–4922. PubMed PMID: 7876266.
  • Hung AY, Haass C, Nitsch RM, et al. Activation of protein kinase C inhibits cellular production of the amyloid beta-protein. J Biol Chem. 1993 Nov 5;268(31):22959–22962. PubMed PMID: 8226807.
  • Farber SA, Nitsch RM, Schulz JG, et al. Regulated secretion of beta-amyloid precursor protein in rat brain. J Neuroscience: Official Journal Soc Neurosci. 1995 Nov;15(11):7442–7451. PubMed PMID: 7472496.
  • Mori F, Lai CC, Fusi F, et al. Cholinesterase inhibitors increase secretion of APPs in rat brain cortex. Neuroreport. 1995 Mar 7;6(4):633–636. PubMed PMID: 7605915.
  • Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol. 2003;552(2):335–344.
  • Yang JL, Weissman L, Bohr VA, et al. Mitochondrial DNA damage and repair in neurodegenerative disorders. DNA Repair. 2008 Jul 1;7(7):1110–1120. PubMed PMID: 18463003; PubMed Central PMCID: PMC2442166.
  • Mosconi L, Berti V, Glodzik L, et al. Pre-clinical detection of Alzheimer’s disease using FDG-PET, with or without amyloid imaging. J Alzheimer’s disease: JAD. 2010;20(3):843–854. . PubMed PMID: 20182025; PubMed Central PMCID: PMC3038340.
  • Butterfield DA, Lange ML. Multifunctional roles of enolase in Alzheimer’s disease brain: beyond altered glucose metabolism. J Neurochem. 2009 Nov;111(4):915–933. . PubMed PMID: 19780894; PubMed Central PMCID: PMC4454338.
  • Butterfield DA, Hardas SS, Lange ML. Oxidatively modified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Alzheimer’s disease: many pathways to neurodegeneration. J Alzheimer’s disease: JAD. 2010;20(2):369–393. . PubMed PMID: 20164570; PubMed Central PMCID: PMC2922983.
  • Calvo-Ochoa E, Arias C. Cellular and metabolic alterations in the hippocampus caused by insulin signalling dysfunction and its association with cognitive impairment during aging and Alzheimer’s disease: studies in animal models. Diabetes Metab Res Rev. 2015 Jan;31(1):1–13. . PubMed PMID: 24464982.
  • Wong-Riley M, Antuono P, Ho KC, et al. Cytochrome oxidase in Alzheimer’s disease: biochemical, histochemical, and immunohistochemical analyses of the visual and other systems. Vision Res. 1997 Dec;37(24):3593–3608. PubMed PMID: 9425533.
  • Rhein V, Song X, Wiesner A, et al. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20057–20062. PubMed PMID: 19897719; PubMed Central PMCID: PMC2774257.
  • Medeiros R, LaFerla FM. Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp Neurol. 2013 Jan;239:133–138. PubMed PMID: 23063604.
  • Bamberger ME, Harris ME, McDonald DR, et al. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neuroscience: Official Journal Soc Neurosci. 2003 Apr 1;23(7):2665–2674. PubMed PMID: 12684452.
  • Stewart CR, Stuart LM, Wilkinson K, et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol. 2010 Feb;11(2):155–161. PubMed PMID: 20037584; PubMed Central PMCID: PMC2809046.
  • Liu Y, Walter S, Stagi M, et al. LPS receptor (CD14): a receptor for phagocytosis of Alzheimer’s amyloid peptide. Brain: a J Neurol. 2005 Aug;128(Pt 8):1778–1789. PubMed PMID: 15857927.
  • Fricker M, Vilalta A, Tolkovsky AM, et al. Caspase inhibitors protect neurons by enabling selective necroptosis of inflamed microglia. J Biol Chem. 2013 Mar 29;288(13):9145–9152. PubMed PMID: 23386613; PubMed Central PMCID: PMC3610987.
  • Burguillos MA, Deierborg T, Kavanagh E, et al. Caspase signalling controls microglia activation and neurotoxicity. Nature. 2011 Apr 21;472(7343):319–324. PubMed PMID: 21389984.
  • Frank S, Burbach GJ, Bonin M, et al. TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice. Glia. 2008 Oct;56(13):1438–1447. PubMed PMID: 18551625.
  • Hsieh CL, Koike M, Spusta SC, et al. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem. 2009 May;109(4):1144–1156. PubMed PMID: 19302484; PubMed Central PMCID: PMC3087597.
  • Bradshaw EM, Chibnik LB, Keenan BT, et al. CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat Neurosci. 2013 Jul;16(7):848–850. PubMed PMID: 23708142; PubMed Central PMCID: PMC3703870.
  • Streit WJ, Braak H, Xue QS, et al. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol. 2009 Oct;118(4):475–485. PubMed PMID: 19513731; PubMed Central PMCID: PMC2737117.
  • Krabbe G, Halle A, Matyash V, et al. Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PloS one. 2013;8(4):e60921. . PubMed PMID: 23577177; PubMed Central PMCID: PMC3620049.
  • Flanary BE, Sammons NW, Nguyen C, et al. Evidence that aging and amyloid promote microglial cell senescence. Rejuvenation Res. 2007;10(1):61–74.
  • Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci. 2008;28(33):8354–8360.
  • Lucin KM, O’Brien CE, Bieri G, et al. Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer’s disease. Neuron. 2013 Sep 4;79(5):873–886. PubMed PMID: 24012002; PubMed Central PMCID: PMC3779465.
  • Woo MS, Park JS, Choi IY, et al. Inhibition of MMP‐3 or‐9 suppresses lipopolysaccharide‐induced expression of proinflammatory cytokines and iNOS in microglia. J Neurochem. 2008;106(2):770–780.
  • Fujioka H, Dairyo Y, Yasunaga K-I, et al. Neural functions of matrix metalloproteinases: plasticity, neurogenesis, and disease. Biochem Res Int [article:789083]. 2012;2012:1–8.
  • Pagenstecher A, Stalder AK, Kincaid CL, et al. Differential expression of matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase genes in the mouse central nervous system in normal and inflammatory states. Am J Pathol. 1998;152(3):729.
  • Yong VW, Power C, Forsyth P, et al. Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci. 2001;2(7):502.
  • Nuttall RK, Silva C, Hader W, et al. Metalloproteinases are enriched in microglia compared with leukocytes and they regulate cytokine levels in activated microglia. Glia. 2007;55(5):516–526.
  • Yin K-J, Cirrito JR, Yan P, et al. Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-β peptide catabolism. J Neurosci. 2006;26(43):10939–10948.
  • Yan P, Hu X, Song H, et al. Matrix metalloproteinase-9 degrades amyloid-β fibrils in vitro and compact plaques in situ. J Biol Chem. 2006;281(34):24566–24574.
  • Miners JS, Baig S, Palmer J, et al. SYMPOSIUM: clearance of Aβ from the Brain in Alzheimer’s Disease: aβ‐degrading enzymes in Alzheimer’s disease. Brain Pathology. 2008;18(2):240–252.
  • Lorenzl S, Büerger K, Hampel H, et al. Profiles of matrix metalloproteinases and their inhibitors in plasma of patients with dementia. Int Psychogeriatrics. 2008;20(1):67–76.
  • Asahina M, Yoshiyama Y, Hattori T. Expression of matrix metalloproteinase-9 and urinary-type plasminogen activator in Alzheimer’s disease brain. Clin Neuropathol. 2001;20(2):60–63.
  • Deb S, Zhang JW, Gottschall PE. β-Amyloid induces the production of active, matrix-degrading proteases in cultured rat astrocytes. Brain Res. 2003;970(1–2):205–213.
  • Li W, Poteet E, Xie L, et al. Regulation of matrix metalloproteinase 2 by oligomeric amyloid β protein. Brain Res. 2011;1387:141–148.
  • Wang -X-X, Tan M-S, Yu J-T, et al. Matrix metalloproteinases and their multiple roles in Alzheimer’s disease. Biomed Res Int [article:908636]. 2014;2014:1–8.
  • Saarela MS, Lehtimäki T, Rinne JO, et al. Interaction between matrix metalloproteinase 3 and the ε4 allele of apolipoprotein E increases the risk of Alzheimer’s disease in Finns. Neurosci Lett. 2004;367(3):336–339.
  • Liebig J. Über Kynurensäure. Eur J Org Chem. 1853;86(1):125–126.
  • Amori L, Guidetti P, Pellicciari R, et al. On the relationship between the two branches of the KP in the rat brain in vivo. J Neurochem. 2009 Apr;109(2):316–325. PubMed PMID: 19226371; PubMed Central PMCID: PMC3666345.
  • Wolf H. The effect of hormones and vitamin B6 on urinary excretion of metabolites of the KP. Scand J Clin Lab Invest Supplementum. 1974;136:1–186. PubMed PMID: 4275489.
  • Bender DA, McCreanor GM. The preferred route of kynurenine metabolism in the rat. Biochim Biophys Acta. 1982 Jul 16;717(1):56–60. PubMed PMID: 7104391.
  • Moroni F. Tryptophan metabolism and brain function: focus on kynurenine and other indole metabolites. Eur J Pharmacol. 1999 Jun 30;375(1–3):87–100. PubMed PMID: 10443567.
  • McMenamy RH. Binding of indole analogues to human serum albumin. Effects of fatty acids. J Biol Chem. 1965 Nov;240(11):4235–4243. PubMed PMID: 5845825.
  • Madras BK, Cohen EL, Messing R, et al. Relevance of free tryptophan in serum to tissue tryptophan concentrations. Metabolism. 1974 Dec;23(12):1107–1116. PubMed PMID: 4427559.
  • Pardridge WM. Brain metabolism: a perspective from the blood-brain barrier. Physiol Rev. 1983 Oct;63(4):1481–1535. . PubMed PMID: 6361813.
  • Boado RJ, Li JY, Nagaya M, et al. Selective expression of the large neutral amino acid transporter at the blood-brain barrier. Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12079–12084. PubMed PMID: 10518579; PubMed Central PMCID: PMC18415.
  • Pardridge WM, Fierer G. Transport of tryptophan into brain from the circulating, albumin-bound pool in rats and in rabbits. J Neurochem. 1990 Mar;54(3):971–976. PubMed PMID: 2303823.
  • Smith QR, Momma S, Aoyagi M, et al. Kinetics of neutral amino acid transport across the blood-brain barrier. J Neurochem. 1987 Nov;49(5):1651–1658. PubMed PMID: 3668544.
  • Fernstrom JD. Branched-chain amino acids and brain function. J Nutr. 2005 Jun;135(6 Suppl):1539S–46S. PubMed PMID: 15930466.
  • Kennett GA, Curzon G, Hunt A, et al. Immobilization decreases amino acid concentrations in plasma but maintains or increases them in brain. J Neurochem. 1986 Jan;46(1):208–212. PubMed PMID: 3940281.
  • O’Kane RL, Hawkins RA. Na+-dependent transport of large neutral amino acids occurs at the abluminal membrane of the blood-brain barrier. Am J Physiol Endocrinol Metabol. 2003 Dec;285(6):E1167–73. . PubMed PMID: 12933350.
  • Bender DA. Biochemistry of tryptophan in health and disease. Mol Aspects Med. 1983;6(2):101–197.
  • Schwarcz R, Whetsell WO Jr., Mangano RM. Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science. 1983 Jan 21;219(4582):316–318. PubMed PMID: 6849138.
  • Heyes MP, Achim CL, Wiley CA, et al. Human microglia convert l-tryptophan into the neurotoxin quinolinic acid. Biochem J. 1996 Dec 1;320(Pt 2):595–597. PubMed PMID: 8973572; PubMed Central PMCID: PMC1217971.
  • Espey MG, Chernyshev ON, Reinhard JF Jr., et al. Activated human microglia produce the excitotoxin quinolinic acid. Neuroreport. 1997 Jan 20;8(2):431–434. PubMed PMID: 9080423.
  • Guillemin GJ, Smythe G, Takikawa O, et al. Expression of indoleamine 2,3-dioxygenase and production of QUIN by human microglia, astrocytes, and neurons. Glia. 2005 Jan 1;49(1):15–23. PubMed PMID: 15390107.
  • Sattler R, Tymianski M. Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death. Mol Neurobiol. 2001 Aug-Dec;24(1–3):107–129. . PubMed PMID: 11831548.
  • Chang YC, Kim HW, Rapoport SI, et al. Chronic NMDA administration increases neuroinflammatory markers in rat frontal cortex: cross-talk between excitotoxicity and neuroinflammation. Neurochem Res. 2008 Nov;33(11):2318–2323. PubMed PMID: 18500552; PubMed Central PMCID: PMC2574932.
  • Braidy N, Grant R, Adams S, et al. Mechanism for QUIN cytotoxicity in human astrocytes and neurons. Neurotox Res. 2009 Jul;16(1):77–86. PubMed PMID: 19526301.
  • Tavares RG, Tasca CI, Santos CE, et al. QUIN inhibits glutamate uptake into synaptic vesicles from rat brain. Neuroreport. 2000 Feb 7;11(2):249–253. PubMed PMID: 10674464.
  • Tavares RG, Tasca CI, Santos CE, et al. QUIN stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes. Neurochem Int. 2002 Jun;40(7):621–627. PubMed PMID: 11900857.
  • Ting KK, Brew BJ, Guillemin GJ. Effect of QUIN on human astrocytes morphology and functions: implications in Alzheimer’s disease. J Neuroinflammation. 2009 Dec 10;6:36. . PubMed PMID: 20003262; PubMed Central PMCID: PMC2797503.
  • Butterfield DA, Hensley K, Cole P, et al. Oxidatively induced structural alteration of glutamine synthetase assessed by analysis of spin label incorporation kinetics: relevance to Alzheimer’s disease. J Neurochem. 1997;68(6):2451–2457.
  • Hensley K, Hall N, Subramaniam R, et al. Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. J Neurochem. 1995;65(5):2146–2156.
  • Rios C, Santamaria A. QUIN is a potent lipid peroxidant in rat brain homogenates. Neurochem Res. 1991;16(10):1139–1143.
  • Goda K, Kishimoto R, Shimizu S, et al. QUIN and active oxygens. Possible contribution of active oxygens during cell death in the brain. Adv Exp Med Biol. 1996;398:247–254. PubMed PMID: 8906272.
  • Stipek S, Stastny F, Platenik J, et al. The effect of quinolinate on rat brain lipid peroxidation is dependent on iron. Neurochem Int. 1997 Feb;30(2):233–237. PubMed PMID: 9017671.
  • Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med. 1991;11(1):81–128. PubMed PMID: 1937131.
  • Porter NA, Caldwell SE, Mills KA. Mechanisms of free radical oxidation of unsaturated lipids. Lipids. 1995 Apr;30(4):277–290. PubMed PMID: 7609594.
  • Mattson MP. Modification of ion homeostasis by lipid peroxidation: roles in neuronal degeneration and adaptive plasticity. Trends Neurosci. 1998 Feb;21(2):53–57. PubMed PMID: 9498297.
  • Keller JN, Mattson MP. Roles of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction, and death in the nervous system. Rev Neurosci. 1998;9(2):105–116. PubMed PMID: 9711902.
  • Lovell MA, Ehmann WD, Butler SM, et al. Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease. Neurology. 1995 Aug;45(8):1594–1601. PubMed PMID: 7644059.
  • Markesbery WR, Lovell MA. Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer’s disease. Neurobiol Aging. 1998 Jan-Feb;19(1):33–36. PubMed PMID: 9562500.
  • Montine KS, Olson SJ, Amarnath V, et al. Immunohistochemical detection of 4-hydroxy-2-nonenal adducts in Alzheimer’s disease is associated with inheritance of APOE4. Am J Pathol. 1997 Feb;150(2):437–443. PubMed PMID: 9033259; PubMed Central PMCID: PMC1858275.
  • Montine KS, Reich E, Neely MD, et al. Distribution of reducible 4-hydroxynonenal adduct immunoreactivity in Alzheimer disease is associated with APOE genotype. J Neuropathol Exp Neurol. 1998 May;57(5):415–425. PubMed PMID: 9596412.
  • Lovell MA, Ehmann WD, Mattson MP, et al. Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer’s disease. Neurobiol Aging. 1997 Sep-Oct;18(5):457–461. PubMed PMID: 9390770.
  • Rahman A, Ting K, Cullen KM, et al. The excitotoxin QUIN induces tau phosphorylation in human neurons. PloS one. 2009 Jul 22;4(7):e6344. PubMed PMID: 19623258; PubMed Central PMCID: PMC2709912.
  • Chan SF, Sucher NJ. An NMDA receptor signaling complex with protein phosphatase 2A. J Neuroscience: Official Journal Soc Neurosci. 2001 Oct 15;21(20):7985–7992. PubMed PMID: 11588171.
  • Rossi F, Schwarcz R, Rizzi M. Curiosity to kill the KAT (kynurenine aminotransferase): structural insights into brain KYNA synthesis. Curr Opin Struct Biol. 2008 Dec;18(6):748–755. . PubMed PMID: 18950711.
  • Hodgkins PS, Wu HQ, Zielke HR, et al. 2-Oxoacids regulate KYNA production in the rat brain: studies in vitro and in vivo. J Neurochem. 1999 Feb;72(2):643–651. PubMed PMID: 9930736.
  • Chess AC, Simoni MK, Alling TE, et al. Elevations of endogenous KYNA produce spatial working memory deficits. Schizophr Bull. 2007 May;33(3):797–804. PubMed PMID: 16920787; PubMed Central PMCID: PMC2526148.
  • Chess AC, Bucci DJ. Increased concentration of cerebral KYNA alters stimulus processing and conditioned responding. Behav Brain Res. 2006 Jun 30;170(2):326–332. . PubMed PMID: 16621049.
  • Alexander KS, Wu HQ, Schwarcz R, et al. Acute elevations of brain KYNA impair cognitive flexibility: normalization by the alpha7 positive modulator galantamine. Psychopharmacology. 2012 Apr;220(3):627–637. PubMed PMID: 22038535; PubMed Central PMCID: PMC3666324.
  • Pocivavsek A, Wu HQ, Potter MC, et al. Fluctuations in endogenous KYNA control hippocampal glutamate and memory. Neuropsychopharmacol: off Publ Am Coll Neuropsychopharmacol. 2011 Oct;36(11):2357–2367. PubMed PMID: 21796108; PubMed Central PMCID: PMC3176574.
  • Stone TW. Neuropharmacology of quinolinic and KYNAs. Pharmacol Rev. 1993;45(3):309–379.
  • Kessler M, Terramani T, Lynch G, et al. A glycine site associated with N‐methyl‐D‐aspartic acid receptors: characterization and identification of a new class of antagonists. J Neurochem. 1989;52(4):1319–1328.
  • Leveille F, El Gaamouch F, Gouix E, et al. Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors. FASEB Journal: off Publ Federation Am Soc Exp Biol. 2008 Dec;22(12):4258–4271. PubMed PMID: 18711223.
  • Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci. 2002 May;5(5):405–414. . PubMed PMID: 11953750.
  • Alkondon M, Pereira EF, Eisenberg HM, et al. Age dependency of inhibition of alpha7 nicotinic receptors and tonically active N-methyl-D-aspartate receptors by endogenously produced KYNA in the brain. J Pharmacol Exp Ther. 2011 Jun;337(3):572–582. . PubMed PMID: 21270133; PubMed Central PMCID: PMC3101010.
  • Wu HQ, Lee SC, Scharfman HE, et al. L-4-chlorokynurenine attenuates kainate-induced seizures and lesions in the rat. Exp Neurol. 2002 Sep;177(1):222–232. PubMed PMID: 12429224.
  • Lee SC, Schwarcz R. Excitotoxic injury stimulates pro-drug-induced 7-chlorokynurenate formation in the rat striatum in vivo. Neurosci Lett. 2001 May 25;304(3):185–188. PubMed PMID: 11343833.
  • Hilmas C, Pereira EF, Alkondon M, et al. The brain metabolite KYNA inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neuroscience: Official Journal Soc Neurosci. 2001 Oct 1;21(19):7463–7473. PubMed PMID: 11567036.
  • Alkondon M, Pereira EF, Yu P, et al. Targeted deletion of the kynurenine aminotransferase ii gene reveals a critical role of endogenous KYNA in the regulation of synaptic transmission via alpha7 nicotinic receptors in the hippocampus. J Neuroscience: Official Journal Soc Neurosci. 2004 May 12;24(19):4635–4648. PubMed PMID: 15140935.
  • Lopes C, Pereira EF, Wu HQ, et al. Competitive antagonism between the nicotinic allosteric potentiating ligand galantamine and KYNA at alpha7* nicotinic receptors. J Pharmacol Exp Ther. 2007 Jul;322(1):48–58. PubMed PMID: 17446300.
  • Dineley KT, Pandya AA, Yakel JL. Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharmacol Sci. 2015 Feb;36(2):96–108. . PubMed PMID: 25639674; PubMed Central PMCID: PMC4324614.
  • Nagele RG, D’Andrea MR, Anderson WJ, et al. Intracellular accumulation of beta-amyloid(1–42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer’s disease. Neuroscience. 2002;110(2):199–211. PubMed PMID: 11958863.
  • Wang HY, Li W, Benedetti NJ, et al. Alpha 7 nicotinic acetylcholine receptors mediate beta-amyloid peptide-induced tau protein phosphorylation. J Biol Chem. 2003 Aug 22;278(34):31547–31553. PubMed PMID: 12801934.
  • Dziewczapolski G, Glogowski CM, Masliah E, et al. Deletion of the alpha 7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer’s disease. J Neuroscience: Official Journal Soc Neurosci. 2009 Jul 8;29(27):8805–8815. PubMed PMID: 19587288; PubMed Central PMCID: PMC2753494.
  • Mousavi M, Hellstrom-Lindahl E. Nicotinic receptor agonists and antagonists increase sAPPalpha secretion and decrease Abeta levels in vitro. Neurochem Int. 2009 Mar-Apr;54(3–4):237–244. . PubMed PMID: 19111588.
  • Anderson SM, Brunzell DH. Low dose nicotine and antagonism of beta2 subunit containing nicotinic acetylcholine receptors have similar effects on affective behavior in mice. PloS one. 2012;7(11):e48665. . PubMed PMID: 23144922; PubMed Central PMCID: PMC3492489.
  • Levin ED, Caldwell DP. Low-dose mecamylamine improves learning of rats in the radial-arm maze repeated acquisition procedure. Neurobiol Learn Mem. 2006 Jul;86(1):117–122. . PubMed PMID: 16632386.
  • Hahn B, Shoaib M, Stolerman IP. Selective nicotinic receptor antagonists: effects on attention and nicotine-induced attentional enhancement. Psychopharmacology. 2011 Sep;217(1):75–82. . PubMed PMID: 21432025.
  • Danysz W, Parsons CG, Mobius HJ, et al. Neuroprotective and symptomatological action of memantine relevant for Alzheimer’s disease–a unified glutamatergic hypothesis on the mechanism of action. Neurotox Res. 2000;2(2–3):85–97. PubMed PMID: 16787834.
  • Aracava Y, Pereira EF, Maelicke A, et al. Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons. J Pharmacol Exp Ther. 2005 Mar;312(3):1195–1205. PubMed PMID: 15522999.
  • Beggiato S, Antonelli T, Tomasini MC, et al. KYNA, by targeting alpha7 nicotinic acetylcholine receptors, modulates extracellular GABA levels in the rat striatum in vivo. Eur J Neurosci. 2013 May;37(9):1470–1477. PubMed PMID: 23442092.
  • Dani JA, Bertrand D. Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol. 2007;47:699–729. . PubMed PMID: 17009926.
  • Tepper JM, Abercrombie ED, Bolam JP. Basal ganglia macrocircuits. Prog Brain Res. 2007;160:3–7. . PubMed PMID: 17499105.
  • Azam L, Winzer-Serhan U, Leslie FM. Co-expression of alpha7 and beta2 nicotinic acetylcholine receptor subunit mRNAs within rat brain cholinergic neurons. Neuroscience. 2003;119(4):965–977. PubMed PMID: 12831856.
  • Wu Z, Guo Z, Gearing M, et al. Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s [corrected] disease model. Nat Commun. 2014 Jun;13(5):4159. . PubMed PMID: 24923909; PubMed Central PMCID: PMC4159602.
  • Cosi C, Mannaioni G, Cozzi A, et al. G-protein coupled receptor 35 (GPR35) activation and inflammatory pain: studies on the antinociceptive effects of KYNA and zaprinast. Neuropharmacology. 2011 Jun;60(7–8):1227–1231. PubMed PMID: 21110987.
  • Wang J, Simonavicius N, Wu X, et al. KYNA as a ligand for orphan G protein-coupled receptor GPR35. J Biol Chem. 2006 Aug 4;281(31):22021–22028. PubMed PMID: 16754668.
  • Prescott C, Weeks AM, Staley KJ, et al. KYNA has a dual action on AMPA receptor responses. Neurosci Lett. 2006 Jul 10;402(1–2):108–112. PubMed PMID: 16644124.
  • Rozsa E, Robotka H, Vecsei L, et al. The Janus-face KYNA. J Neural Transm. 2008 Aug;115(8):1087–1091. PubMed PMID: 18446262.
  • Okuda S, Nishiyama N, Saito H, et al. 3-Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. J Neurochem. 1998 Jan;70(1):299–307. PubMed PMID: 9422375.
  • Dykens JA, Sullivan SG, Stern A. Oxidative reactivity of the tryptophan metabolites 3-hydroxyanthranilate, cinnabarinate, quinolinate and picolinate. Biochem Pharmacol. 1987 Jan 15;36(2):211–217. PubMed PMID: 2949752.
  • Szalardy L, Klivenyi P, Zadori D, et al. Mitochondrial disturbances, tryptophan metabolites and neurodegeneration: medicinal chemistry aspects. Curr Med Chem. 2012;19(13):1899–1920. PubMed PMID: 22429096.
  • Halestrap AP, McStay GP, Clarke SJ. The permeability transition pore complex: another view. Biochimie. 2002 Feb-Mar;84(2–3):153–166. PubMed PMID: 12022946.
  • Halestrap AP. The mitochondrial permeability transition: its molecular mechanism and role in reperfusion injury. Biochem Soc Symp. 1999;66:181–203. PubMed PMID: 10989667.
  • Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997 Nov 14;91(4):479–489. PubMed PMID: 9390557.
  • Lee HJ, Bach JH, Chae HS, et al. Mitogen-activated protein kinase/extracellular signal-regulated kinase attenuates 3-hydroxykynurenine-induced neuronal cell death. J Neurochem. 2004 Feb;88(3):647–656. PubMed PMID: 14720214.
  • Bernardi P, Scorrano L, Colonna R, et al. Mitochondria and cell death. Mechanistic aspects and methodological issues. Eur J Biochem. 1999 Sep;264(3):687–701. PubMed PMID: 10491114.
  • Chiarugi A, Meli E, Moroni F. Similarities and differences in the neuronal death processes activated by 3OH-kynurenine and quinolinic acid. J Neurochem. 2001 Jun;77(5):1310–1318. PubMed PMID: 11389182.
  • Guidetti P, Schwarcz R. 3-Hydroxykynurenine potentiates quinolinate but not NMDA toxicity in the rat striatum. Eur J Neurosci. 1999;Nov;11(11):3857–3863. PubMed PMID: 10583474.
  • Esaki H, Onozaki H, Kawakishi S, et al. New antioxidant isolated from tempeh. J Agric Food Chem. 1996;44(3):696–700.
  • Christen S, Peterhans E, Stocker R. Antioxidant activities of some tryptophan metabolites: possible implication for inflammatory diseases. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2506–2510. PubMed PMID: 2320571; PubMed Central PMCID: PMC53718.
  • Leipnitz G, Schumacher C, Dalcin KB, et al. In vitro evidence for an antioxidant role of 3-hydroxykynurenine and 3-hydroxyanthranilic acid in the brain. Neurochem Int. 2007 Jan;50(1):83–94. PubMed PMID: 16959377.
  • Backhaus C, Rahman H, Scheffler S, et al. NO scavenging by 3-hydroxyanthranilic acid and 3-hydroxykynurenine: N-nitrosation leads via oxadiazoles to o-quinone diazides. Nitric Oxide. 2008;19(3):237–244.
  • Michalowska M, Znorko B, Kaminski T, et al. New insights into tryptophan and its metabolites in the regulation of bone metabolism. J Physiol Pharmacol. 2015;66(6):779–791.
  • Stone TW, Stoy N, Darlington LG. An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol Sci. 2013;34(2):136–143.
  • Chen Y, Guillemin GJ. KP metabolites in humans: disease and healthy states. Int J Tryptophan Res: IJTR. 2009;2:1.
  • Chobot V, Hadacek F, Weckwerth W, et al. Iron chelation and redox chemistry of anthranilic acid and 3-hydroxyanthranilic acid: A comparison of two structurally related KP metabolites to obtain improved insights into their potential role in neurological disease development. J Organomet Chem. 2015;782:103–110.
  • Santana CS, Aguiar A. Effect of biological mediator, 3-hydroxyanthranilic acid, in dye decolorization by Fenton processes. Int Biodeterior Biodegradation. 2015;104:1–7.
  • Kamnev AA, Kuzmann E. Mössbauer spectroscopic evidence for the reduction of iron (III) by anthranilic acid in aqueous solution. Polyhedron. 1997;16(19):3353–3356.
  • Dazzi C, Candiano G, Massazza S, et al. New high-performance liquid chromatographic method for the detection of picolinic acid in biological fluids. J Chromatogr B, Biomed Sci Appl. 2001 Feb 10;751(1):61–68. PubMed PMID: 11232856.
  • Smythe GA, Braga O, Brew BJ, et al. Concurrent quantification of quinolinic, picolinic, and nicotinic acids using electron-capture negative-ion gas chromatography-mass spectrometry. Anal Biochem. 2002 Feb 1;301(1):21–26. PubMed PMID: 11811963.
  • Rebello T, Lonnerdal B, Hurley LS. Picolinic acid in milk, pancreatic juice, and intestine: inadequate for role in zinc absorption. Am J Clin Nutr. 1982 Jan;35(1):1–5. PubMed PMID: 7064867.
  • Mehler AH. Formation of picolinic and quinolinic acids following enzymatic oxidation of 3-hydroxyanthranilic acid. J Biol Chem. 1956 Jan;218(1):241–254. PubMed PMID: 13278331.
  • Smart TG, Xie X, Krishek BJ. Modulation of inhibitory and excitatory amino acid receptor ion channels by zinc. Prog Neurobiol. 1994 Feb;42(3):393–441. PubMed PMID: 7520185.
  • Jhamandas KH, Boegman RJ, Beninger RJ, et al. Role of zinc in blockade of excitotoxic action of QUIN by picolinic acid. Amino Acids. 1998;14(1–3):257–261. PubMed PMID: 9871471.
  • Suzuki K, Yasuda M, Yamasaki K. Stability constants of picolinic and quinaldic acid chelates of bivalent metals. J Phys Chem. 1957;61(2):229–231.
  • Lee P, Jhamandas K, Boegman R, et al. editors. Zinc chelators inhibit excitotoxic action of QUIN on basal forebrain cholinergic neurons. Soc Neurosci Abstr. 1996;22:806.
  • Cockhill J, Jhamandas K, Boegman RJ, et al. Action of picolinic acid and structurally related pyridine carboxylic acids on quinolinic acid-induced cortical cholinergic damage. Brain Res. 1992 Dec 18;599(1):57–63. PubMed PMID: 1493549.
  • Berger SJ, Sudar DC, Berger NA. Metabolic consequences of DNA damage: DNA damage induces alterations in glucose metabolism by activation of poly (ADP-ribose) polymerase. Biochem Biophys Res Commun. 1986 Jan 14;134(1):227–232. PubMed PMID: 3080986.
  • Ha HC, Snyder SH. Poly(ADP-ribose) polymerase-1 in the nervous system. Neurobiol Dis. 2000 Aug 7;7(4):225–239. PubMed PMID: 10964595.
  • Tan PH, Bharath AK. Manipulation of indoleamine 2,3 dioxygenase; a novel therapeutic target for treatment of diseases. Expert Opin Ther Targets. 2009 Aug;13(8):987–1012. . PubMed PMID: 19534572.
  • Braidy N, Guillemin GJ, Grant R. Effects of KP inhibition on NAD+ metabolism and cell viability in human primary astrocytes and neurons. Int J Tryptophan Res. 2011;4(IJTR):S7052.
  • Braidy N, Grant R, Brew BJ, et al. Effects of KP metabolites on intracellular NAD synthesis and cell death in human primary astrocytes and neurons. Int J Tryptophan Res: IJTR. 2009;2:61–69. PubMed PMID: 22084582; PubMed Central PMCID: PMC3195228.
  • Gong B, Pan Y, Vempati P, et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models. Neurobiol Aging. 2013;34(6):1581–1588.
  • Kotake Y, Masayama T. Uber den mechanismus der Kynurenine-building aus Tryptophan. Hoppe-Seyler’s Z Physiol Cehm. 1937;243:237–244.
  • Comings DE, Muhleman D, Dietz G, et al. Sequence of human tryptophan 2, 3-dioxygenase (TDO2): presence of a glucocorticoid response-like element composed of a GTT repeat and an intronic CCCCT repeat. Genomics. 1995;29(2):390–396.
  • Hirata F, Hayaishi O. New degradative routes of 5-hydroxytryptophan and serotonin by intestinal tryptophan 2, 3-dioxygenase. Biochem Biophys Res Commun. 1972;47(5):1112–1119.
  • Britan A, Maffre V, Tone S, et al. Quantitative and spatial differences in the expression of tryptophan-metabolizing enzymes in mouse epididymis. Cell Tissue Res. 2006 May;324(2):301–310. PubMed PMID: 16450123.
  • Minatogawa Y, Suzuki S, Ando Y, et al. Tryptophan pyrrole ring cleavage enzymes in placenta. Adv Exp Med Biol. 2003;527:425–434. PubMed PMID: 15206760.
  • Haber R, Bessette D, Hulihan-Giblin B, et al. Identification of tryptophan 2,3-dioxygenase RNA in rodent brain. J Neurochem. 1993 Mar;60(3):1159–1162. PubMed PMID: 7679723.
  • Tatsumi K, Higuchi T, Fujiwara H, et al. Induction of tryptophan 2,3-dioxygenase in the mouse endometrium during implantation. Biochem Biophys Res Commun. 2000 Jul 21;274(1):166–170. PubMed PMID: 10903913.
  • Schutz G, Killewich L, Chen G, et al. Control of the mRNA for hepatic tryptophan oxygenase during hormonal and substrate induction. Proc Natl Acad Sci. 1975;72(3):1017–1020.
  • Wolf H, Rr BROWN. Studies on tryptophan metabolism in male subjects treated with hydrocortisone. J Clin Endocrinol Metabolism. 1971;33(5):838–843.
  • Knox W, Mehler AH. The adaptive increase of the tryptophan peroxidase-oxidase system of liver. Sci (Washington). 1951;113:237–238.
  • Nakamura T, Shinno H, Ichihara A. Insulin and glucagon as a new regulator system for tryptophan oxygenase activity demonstrated in primary cultured rat hepatocytes. J Biol Chem. 1980;255(16):7533–7535.
  • Braidman IP, Rose D. Effects of sex hormones on three glucocorticoid-inducible enzymes concerned with amino acid metabolism in rat liver. Endocrinology. 1971;89(5):1250–1255.
  • Batabyal D, Yeh S-R. Human tryptophan dioxygenase: a comparison to indoleamine 2, 3-dioxygenase. J Am Chem Soc. 2007;129(50):15690–15701.
  • Thackray SJ, Mowat CG, Chapman SK. Exploring the mechanism of tryptophan 2, 3-dioxygenase. London: Portland Press Limited; 2008.
  • Yamamoto S, Hayaishi O. Tryptophan pyrrolase of rabbit intestine d-and l-tryptophan-cleaving enzyme or enzymes. J Biol Chem. 1967;242(22):5260–5266.
  • Shimizu T, Nomiyama S, Hirata F, et al. Indoleamine 2,3-dioxygenase. Purification and some properties. J Biol Chem. 1978 Jul 10;253(13):4700–4706. PubMed PMID: 26687.
  • Pfefferkorn ER, Guyre PM. Inhibition of growth of Toxoplasma gondii in cultured fibroblasts by human recombinant gamma interferon. Infect Immun. 1984 May;44(2):211–216. PubMed PMID: 6425215; PubMed Central PMCID: PMC263502.
  • Werner-Felmayer G, Werner ER, Fuchs D, et al. Neopterin formation and tryptophan degradation by a human myelomonocytic cell line (THP-1) upon cytokine treatment. Cancer Res. 1990 May 15;50(10):2863–2867. PubMed PMID: 2110500.
  • Yamada A, Akimoto H, Kagawa S, et al. Proinflammatory cytokine interferon-gamma increases induction of indoleamine 2,3-dioxygenase in monocytic cells primed with amyloid beta peptide 1–42: implications for the pathogenesis of Alzheimer’s disease. J Neurochem. 2009 Aug;110(3):791–800. PubMed PMID: 19457071.
  • Murray MF. The human indoleamine 2,3-dioxygenase gene and related human genes. Curr Drug Metab. 2007 Apr;8(3):197–200. PubMed PMID: 17430106.
  • Ball HJ, Sanchez-Perez A, Weiser S, et al. Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice. Gene. 2007 Jul 1;396(1):203–213. PubMed PMID: 17499941.
  • Metz R, Duhadaway JB, Kamasani U, et al. Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Res. 2007 Aug 1;67(15):7082–7087. PubMed PMID: 17671174.
  • Yuasa HJ, Takubo M, Takahashi A, et al. Evolution of vertebrate indoleamine 2,3-dioxygenases. J Mol Evol. 2007 Dec;65(6):705–714. PubMed PMID: 18026683.
  • Akimoto H, Yamada A, Takikawa O, editors. Up-regulation of the brain indoleamine 2, 3-dioxygenase activity in a mouse model of Alzheimer’s disease by systemic endotoxin challenge. Int Congress Ser. 2007;1304:357–361;Elsevier.
  • Mazarei G, Budac D, Lu G, et al. The absence of indoleamine 2, 3-dioxygenase expression protects against NMDA receptor-mediated excitotoxicity in mouse brain. Exp Neurol. 2013;249:144–148.
  • Han Q, Robinson H, Cai T, et al. Biochemical and structural properties of mouse kynurenine aminotransferase III. Mol Cell Biol. 2009 Feb;29(3):784–793. PubMed PMID: 19029248; PubMed Central PMCID: PMC2630683.
  • Han Q, Li J, Li J. pH dependence, substrate specificity and inhibition of human kynurenine aminotransferase I. Eur J Biochem. 2004 Dec;271(23–24):4804–4814. . PubMed PMID: 15606768.
  • Yu P, Di Prospero NA, Sapko MT, et al. Biochemical and phenotypic abnormalities in kynurenine aminotransferase II-deficient mice. Mol Cell Biol. 2004 Aug;24(16):6919–6930. PubMed PMID: 15282294; PubMed Central PMCID: PMC479723.
  • Guidetti P, Amori L, Sapko MT, et al. Mitochondrial aspartate aminotransferase: a third kynurenate-producing enzyme in the mammalian brain. J Neurochem. 2007 Jul;102(1):103–111. PubMed PMID: 17442055.
  • Schwarcz R, Bruno JP, Muchowski PJ, et al. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Reviews Neurosci. 2012 Jul;13(7):465–477. PubMed PMID: 22678511; PubMed Central PMCID: PMC3681811.
  • Guillemin GJ, Kerr SJ, Smythe GA, et al. KP metabolism in human astrocytes. Adv Exp Med Biol. 1999;467:125–131. PubMed PMID: 10721049.
  • Heyes MP, Saito K, Markey SP. Human macrophages convert L-tryptophan into the neurotoxin quinolinic acid. Biochem J. 1992 May 1;283(Pt 3):633–635. PubMed PMID: 1534219; PubMed Central PMCID: PMC1130930.
  • van Berkel WJ, Kamerbeek NM, Fraaije MW. Flavoprotein monooxygenases, a diverse class of oxidative biocatalysts. J Biotechnol. 2006 Aug 5;124(4):670–689. . PubMed PMID: 16712999.
  • Amaral M, Levy C, Heyes DJ, et al. Structural basis of kynurenine 3-monooxygenase inhibition. Nature. 2013 Apr 18;496(7445):382–385. PubMed PMID: 23575632; PubMed Central PMCID: PMC3736096.
  • Breton J, Avanzi N, Magagnin S, et al. Functional characterization and mechanism of action of recombinant human kynurenine 3-hydroxylase. Eur J Biochem. 2000 Feb;267(4):1092–1099. PubMed PMID: 10672018.
  • Saito K, Markey SP, Heyes MP. Effects of immune activation on QUIN and neuroactive kynurenines in the mouse. Neuroscience. 1992 Nov;51(1):25–39. PubMed PMID: 1465184.
  • Croitoru-Lamoury J, Guillemin GJ, Dormont D, et al. QUIN up-regulates chemokine production and chemokine receptor expression in astrocytes. In: Developments in tryptophan and serotonin metabolism. Boston,MA: Springer; 2003. p. 37–45.
  • Santamaria A, Rios C, Solis-Hernandez F, et al. Systemic DL-kynurenine and probenecid pretreatment attenuates quinolinic acid-induced neurotoxicity in rats. Neuropharmacology. 1996 Jan;35(1):23–28. PubMed PMID: 8684593.
  • Moroni F, Russi P, Lombardi G, et al. Presence of KYNA in the mammalian brain. J Neurochem. 1988 Jul;51(1):177–180. PubMed PMID: 3379401.
  • Widner B, Leblhuber F, Walli J, et al. Tryptophan degradation and immune activation in Alzheimer’s disease. J Neural Transm. 2000;107(3):343–353. . PubMed PMID: 10821443.
  • Guillemin GJ, Smythe GA, Veas LA, et al. A beta 1–42 induces production of QUIN by human macrophages and microglia. Neuroreport. 2003 Dec 19;14(18):2311–2315. PubMed PMID: 14663182.
  • Souza LC, Jesse CR, Antunes MS, et al. Indoleamine-2,3-dioxygenase mediates neurobehavioral alterations induced by an intracerebroventricular injection of amyloid-beta1–42 peptide in mice. Brain Behav Immun. 2016 Aug;56:363–377. PubMed PMID: 26965653.
  • Blasko I, Marx F, Steiner E, et al. TNFalpha plus IFNgamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs. FASEB Journal: off Publ Federation Am Soc Exp Biol. 1999 Jan;13(1):63–68. PubMed PMID: 9872930.
  • Oh G-S, Pae H-O, Choi B-M, et al. 3-Hydroxyanthranilic acid, one of metabolites of tryptophan via indoleamine 2, 3-dioxygenase pathway, suppresses inducible nitric oxide synthase expression by enhancing heme oxygenase-1 expression. Biochem Biophys Res Commun. 2004;320(4):1156–1162.
  • Sekkai D, Guittet O, Lemaire G, et al. Inhibition of nitric oxide synthase expression and activity in macrophages by 3-hydroxyanthranilic acid, a tryptophan metabolite. Arch Biochem Biophys. 1997 Apr 1;340(1):117–123. PubMed PMID: 9126284.
  • Alberati-Giani D, Malherbe P, Ricciardi-Castagnoli P, et al. Differential regulation of indoleamine 2,3-dioxygenase expression by nitric oxide and inflammatory mediators in IFN-gamma-activated murine macrophages and microglial cells. J Immunol. 1997 Jul 1;159(1):419–426. PubMed PMID: 9200481.
  • Hartai Z, Juhasz A, Rimanoczy A, et al. Decreased serum and red blood cell KYNA levels in Alzheimer’s disease. Neurochem Int. 2007 Jan;50(2):308–313. PubMed PMID: 17023091.
  • Schwarz MJ, Guillemin GJ, Teipel SJ, et al. Increased 3-hydroxykynurenine serum concentrations differentiate Alzheimer’s disease patients from controls. Eur Arch Psychiatry Clin Neurosci. 2013 Jun;263(4):345–352. PubMed PMID: 23192697.
  • Wu W, Nicolazzo JA, Wen L, et al. Expression of tryptophan 2,3-dioxygenase and production of KP metabolites in triple transgenic mice and human Alzheimer’s disease brain. PloS one. 2013;8(4):e59749. . PubMed PMID: 23630570; PubMed Central PMCID: PMC3632609.
  • Koshiguchi M, Komazaki H, Hirai S, et al. Ferulic acid suppresses expression of tryptophan metabolic key enzyme indoleamine 2, 3-dioxygenase via NFkappaB and p38 MAPK in lipopolysaccharide-stimulated microglial cells. Biosci Biotechnol Biochem. 2017 May;81(5):966–971. PubMed PMID: 28077028.
  • Yu D, Tao BB, Yang YY, et al. The IDO inhibitor coptisine ameliorates cognitive impairment in a mouse model of Alzheimer’s disease. J Alzheimer’s disease: JAD. 2015;43(1):291–302. PubMed PMID: 25079795.
  • Pellicciari R, Natalini B, Costantino G, et al. Modulation of the KP in search for new neuroprotective agents. Synthesis and preliminary evaluation of (m-nitrobenzoyl)alanine, a potent inhibitor of kynurenine-3-hydroxylase. J Med Chem. 1994 Mar 4;37(5):647–655. PubMed PMID: 8126705.
  • Speciale C, Wu HQ, Cini M, et al. (R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain KYNA levels in rats. Eur J Pharmacol. 1996 Nov 21;315(3):263–267. PubMed PMID: 8982663.
  • Rover S, Cesura AM, Huguenin P, et al. Synthesis and biochemical evaluation of N-(4-phenylthiazol-2-yl)benzenesulfonamides as high-affinity inhibitors of kynurenine 3-hydroxylase. J Med Chem. 1997 Dec 19;40(26):4378–4385. PubMed PMID: 9435907.
  • Zwilling D, Huang SY, Sathyasaikumar KV, et al. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell. 2011 Jun 10;145(6):863–874. PubMed PMID: 21640374; PubMed Central PMCID: PMC3118409.
  • Moroni F, Cozzi A, Carpendo R, et al. Kynurenine 3-mono-oxygenase inhibitors reduce glutamate concentration in the extracellular spaces of the basal ganglia but not in those of the cortex or hippocampus. Neuropharmacology. 2005 May;48(6):788–795. PubMed PMID: 15829251.
  • Chiarugi A, Carpenedo R, Molina MT, et al. Comparison of the neurochemical and behavioral effects resulting from the inhibition of kynurenine hydroxylase and/or kynureninase. J Neurochem. 1995 Sep;65(3):1176–1183. PubMed PMID: 7643095.
  • Feng Y, Bowden BF, Kapoor V. Ianthellamide A, a selective kynurenine-3-hydroxylase inhibitor from the Australian marine sponge Ianthella quadrangulata. Bioorg Med Chem Lett. 2012 May 15;22(10):3398–3401. . PubMed PMID: 22525315.
  • Saito K, Chen C, Masana M, et al. 4-Chloro-3-hydroxyanthranilate, 6-chlorotryptophan and norharmane attenuate QUIN formation by interferon-γ-stimulated monocytes (THP-1 cells). Biochem J. 1993;291(1):11–14.
  • Walsh J, Todd W, Carpenter B, et al. 4-Halo-3-hydroxyanthranilates are potent inhibitors of 3-hydroxyanthranilate oxygenase in the rat brain in vitro and in vivo. In: Kynurenine and Serotonin pathways. Boston,MA: Springer; 1991. p. 579–582.
  • Todd WP, Carpenter BK, Schwarcz R. Preparation of 4-halo-3-hydroxyanthranilates and demonstration of their inhibition of 3-hydroxyanthranilate oxygenase activity in rat and human brain tissue. Prep Biochem. 1989;19(2):155–165. . PubMed PMID: 2798363.
  • Linderberg M, Hellberg S, Björk S, et al. Synthesis and QSAR of substituted 3-hydroxyanthranilic acid derivatives as inhibitors of 3-hydroxyanthranilic acid dioxygenase (3-HAO). Eur J Med Chem. 1999;34(9):729–744.
  • Walsh HA, Leslie PL, O’Shea KC, et al. 2-Amino-4-[3ʹ-hydroxyphenyl]-4-hydroxybutanoic acid; a potent inhibitor of rat and recombinant human kynureninase. Bioorg Med Chem Lett. 2002 Feb 11;12(3):361–363. PubMed PMID: 11814797.
  • Mattson MP. Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromolecular Med. 2003;3(2):65–94. . PubMed PMID: 12728191.
  • Fukui S, Schwarcz R, Rapoport SI, et al. Blood–brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J Neurochem. 1991;56(6):2007–2017.
  • Scharfman HE, Goodman JH. Effects of central and peripheral administration of KYNA on hippocampal evoked responses in vivo and in vitro. Neuroscience. 1998 Oct;86(3):751–764. PubMed PMID: 9692715.
  • Hokari M, Wu HQ, Schwarcz R, et al. Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chloroKYNA. Neuroreport. 1996 Dec 20;8(1):15–18. PubMed PMID: 9051744.
  • Safety, Tolerability and pharmacokinetics of multiple doses of AV-101 in healthy volunteers. [cited 2018 May 1]. Available from: https://clinicaltrials.gov/ct2/show/NCT01483846
  • van der Goot AT, Zhu W, Vazquez-Manrique RP, et al. Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation. Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14912–14917. PubMed PMID: 22927396; PubMed Central PMCID: PMC3443121.
  • van der Goot AT, Nollen EA. Tryptophan metabolism: entering the field of aging and age-related pathologies. Trends Mol Med. 2013 Jun;19(6):336–344. . PubMed PMID: 23562344.
  • Han Q, Cai T, Tagle DA, et al. Structure, expression, and function of kynurenine aminotransferases in human and rodent brains. Cell Mol Life Sci: CMLS. 2010 Feb;67(3):353–368. PubMed PMID: 19826765; PubMed Central PMCID: PMC2867614.
  • Cooper AJ, Meister A. Comparative studies of glutamine transaminases from rat tissues. Comp Biochem Physiol B: Comp Biochem. 1981;69(2):137–145.
  • Matsuda M, Ogur M. Enzymatic and physiological properties of the yeast glutamate-alpha-ketoadipate transaminase. J Biol Chem. 1969 Oct 10;244(19):5153–5158. PubMed PMID: 5344128.
  • Yu P, Li Z, Zhang L, et al. Characterization of kynurenine aminotransferase III, a novel member of a phylogenetically conserved KAT family. Gene. 2006 Jan;3(365):111–118. . PubMed PMID: 16376499.
  • Han Q, Fang J, Li J. Kynurenine aminotransferase and glutamine transaminase K of Escherichia coli: identity with aspartate aminotransferase. Biochem J. 2001 Dec 15;360(Pt3):617–623. PubMed PMID: 11736651; PubMed Central PMCID: PMC1222264.
  • Perry S, Harries H, Scholfield C, et al. Molecular cloning and expression of a cDNA for human kidney cysteine conjugate beta-lyase. FEBS Lett. 1995 Mar 6;360(3):277–280. PubMed PMID: 7883047.
  • Goh DL, Patel A, Thomas GH, et al. Characterization of the human gene encoding alpha-aminoadipate aminotransferase (AADAT). Mol Genet Metab. 2002 Jul;76(3):172–180. PubMed PMID: 12126930.
  • Martini F, Angelaccio S, Barra D, et al. The primary structure of mitochondrial aspartate aminotransferase from human heart. Biochim Biophys Acta. 1985 Nov 8;832(1):46–51. PubMed PMID: 4052435.
  • Han Q, Robinson H, Cai T, et al. Structural insight into the inhibition of human kynurenine aminotransferase I/glutamine transaminase K. J Med Chem. 2009 May 14;52(9):2786–2793. PubMed PMID: 19338303; PubMed Central PMCID: PMC2844090.
  • Pellicciari R, Rizzo RC, Costantino G, et al. Modulators of the KP of tryptophan metabolism: synthesis and preliminary biological evaluation of (S)-4-(ethylsulfonyl)benzoylalanine, a potent and selective kynurenine aminotransferase II (KAT II) inhibitor. ChemMedChem. 2006 May;1(5):528–531. PubMed PMID: 16892388.
  • Cooper AJ. The role of glutamine transaminase K (GTK) in sulfur and α-keto acid metabolism in the brain, and in the possible bioactivation of neurotoxicants. Neurochem Int. 2004;44(8):557–577.
  • Han Q, Cai T, Tagle DA, et al. Substrate specificity and structure of human aminoadipate aminotransferase/kynurenine aminotransferase II. Biosci Rep. 2008 Aug;28(4):205–215. PubMed PMID: 18620547; PubMed Central PMCID: PMC2559858.
  • Palaiologos G, Hertz L, Schousboe A. Evidence that aspartate aminotransferase activity and ketodicarboxylate carrier function are essential for biosynthesis of transmitter glutamate. J Neurochem. 1988 Jul;51(1):317–320. PubMed PMID: 2898006.
  • Palaiologos G, Hertz L, Schousboe A. Role of aspartate aminotransferase and mitochondrial dicarboxylate transport for release of endogenously and exogenously supplied neurotransmitter in glutamatergic neurons. Neurochem Res. 1989 Apr;14(4):359–366. PubMed PMID: 2569674.
  • Schousboe A, Westergaard N, Sonnewald U, et al. Glutamate and glutamine metabolism and compartmentation in astrocytes. Dev Neurosci. 1993;15(3–5):359–366. PubMed PMID: 7805590.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.