Changing the Face of Kynurenines and Neurotoxicity: Therapeutic Considerations
Abstract
:1. Introduction
2. Common Neurotoxic Mechanisms in Neurodegeneration
3. The Kynurenine Pathway
Kynurenine Pathway Metabolite | Receptorial Effect | References |
---|---|---|
l-Kynurenine | Aryl hydrocarbon receptor (AHR) agonist | [24] |
Kynurenic acid | NMDA receptor antagonist | [36,37] |
Dual effect on AMPA receptors: partial agonist at low nanomolar concentrations; antagonist at high micromolar-millimolar concentrations | [39,40] | |
Kainate receptor antagonist | [38] | |
α7-nicotinic acetylcholine receptor antagonist | [41] | |
G-protein coupled receptor 35 agonist | [42] | |
AHR agonist | [33] | |
Cinnabarinic acid | Type 4 metabotropic glutamate receptor agonist | [60] |
AHR agonist | [61] | |
Quinolinic acid | NMDA agonist | [74] |
4. Kynurenines in Neurodegenerative Diseases
4.1. Alzheimer’s Disease
4.2. Parkinson’s Disease
4.3. Huntington’s Disease
4.4. Amyotrophic Lateral Sclerosis
4.5. Multiple Sclerosis
4.6. Acquired Immunodeficiency Syndrome Dementia Complex
5. Therapeutic Perspectives
Enzyme Inhibitors | Kynurenic Acid Prodrugs or Analogs |
---|---|
3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide (Ro-61-8048) | l-Kynurenine |
2-(3,4-dimethoxybenzenesulfonylamino)-4-(3-nitrophenyl)-5-(piperidin-1-yl)methylthiazole (JM6) | Combination of l-kynurenine and probenecid N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride |
nicotinylalanine | 7-Chlorokynurenic acid |
4-Chlorokynurenine (AV-101) |
6. Conclusions
Acknowledgments
Abbreviations
α7nAch | α7-nicotinic acetylcholine receptor |
AA | anthranilic acid |
Aβ | amyloid β |
ADC | acquired immunodeficiency syndrome dementia complex |
AD | Alzheimer’s disease |
AHR | aryl-hydrocarbon receptor |
AMPA | α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid |
ALS | amyotrophic lateral sclerosis |
CNS | central nervous system |
CSF | cerebrospinal fluid |
GPR35 | G-protein coupled receptor 35 |
HIV-1 | human immunodeficiency virus type 1 |
H2O2 | hydrogen peroxide |
HD | Huntington’s disease |
IDO1 | indoleamine 2,3-dioxygenase 1 |
IDO2 | indoleamine 2,3-dioxygenase 2 |
IFN-β | interferon-β |
IFN-γ | interferon-γ |
KAT | kynurenine aminotransferase |
KMO | kynurenine monooxygenase |
KP | kynurenine pathway |
KYNA | kynurenic acid |
l-KYN | l-kynurenine |
MS | multiple sclerosis |
NAD+ | nicotinamide adenine dinucleotide |
NMDA | N-methyl-d-aspartate |
•NO | nitric oxide |
•NO2 | nitrogen dioxide |
O2•− | superoxide anion |
•OH | hydroxyl radical |
ONOO− | peroxynitrite anion |
PD | Parkinson’s disease |
PIC | picolinic acid |
p-tau | phosphorylated tau |
QUIN | quinolinic acid |
ROS | reactive oxygen species |
RNS | reactive nitrogen species |
SOD1 | superoxide dismutase 1 |
TDO | tryptophan 2,3-dioxygenase |
TRP | tryptophan |
3-HA | 3-hydroxyanthranilic acid |
3-HK | 3-hydroxykynurenine |
3-HAO | 3-hydroxyanthranillic acid oxygenase |
Conflicts of Interest
References
- Block, M.L.; Hong, J.S. Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism. Prog. Neurobiol. 2005, 76, 77–98. [Google Scholar] [CrossRef] [PubMed]
- Gandhi, S.; Abramov, A.Y. Mechanism of oxidative stress in neurodegeneration. Oxid. Med. Cell. Longev. 2012. [Google Scholar] [CrossRef]
- Lau, A.; Tymianski, M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch. 2010, 460, 525–542. [Google Scholar] [CrossRef] [PubMed]
- Vecsei, L.; Szalardy, L.; Fulop, F.; Toldi, J. Kynurenines in the CNS: Recent advances and new questions. Nat. Rev. Drug Discov. 2013, 12, 64–82. [Google Scholar] [CrossRef] [PubMed]
- Sas, K.; Robotka, H.; Toldi, J.; Vecsei, L. Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders. J. Neurol. Sci. 2007, 257, 221–239. [Google Scholar] [CrossRef] [PubMed]
- Novelli, A.; Reilly, J.A.; Lysko, P.G.; Henneberry, R.C. Glutamate becomes neurotoxic via the N-methyl-d-aspartate receptor when intracellular energy levels are reduced. Brain Res. 1988, 451, 205–212. [Google Scholar] [CrossRef] [PubMed]
- Holmstrom, K.M.; Finkel, T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat. Rev. Mol. Cell Biol. 2014, 15, 411–421. [Google Scholar] [CrossRef] [PubMed]
- Kawamata, T.; Akiyama, H.; Yamada, T.; McGeer, P.L. Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am. J. Pathol. 1992, 140, 691–707. [Google Scholar] [PubMed]
- McGeer, P.L.; Itagaki, S.; Boyes, B.E.; McGeer, E.G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 1988, 38, 1285–1291. [Google Scholar] [CrossRef] [PubMed]
- Sapp, E.; Kegel, K.B.; Aronin, N.; Hashikawa, T.; Uchiyama, Y.; Tohyama, K.; Bhide, P.G.; Vonsattel, J.P.; DiFiglia, M. Early and progressive accumulation of reactive microglia in the Huntington disease brain. J. Neuropathol. Exp. Neurol. 2001, 60, 161–172. [Google Scholar] [PubMed]
- Ellrichmann, G.; Reick, C.; Saft, C.; Linker, R.A. The role of the immune system in Huntington’s disease. Clin. Dev. Immunol. 2013. [Google Scholar] [CrossRef]
- Hirsch, E.C.; Hunot, S. Neuroinflammation in Parkinson’s disease: A target for neuroprotection? Lancet Neurol. 2009, 8, 382–397. [Google Scholar] [CrossRef] [PubMed]
- De Felice, F.G.; Velasco, P.T.; Lambert, M.P.; Viola, K.; Fernandez, S.J.; Ferreira, S.T.; Klein, W.L. Aβ oligomers induce neuronal oxidative stress through an N-methyl-d-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J. Biol. Chem. 2007, 282, 11590–11601. [Google Scholar]
- Mattson, M.P.; Cheng, B.; Davis, D.; Bryant, K.; Lieberburg, I.; Rydel, R.E. β-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J. Neurosci. 1992, 12, 376–389. [Google Scholar] [PubMed]
- Wenk, G.L.; Parsons, C.G.; Danysz, W. Potential role of N-methyl-d-aspartate receptors as executors of neurodegeneration resulting from diverse insults: Focus on memantine. Behav. Pharmacol. 2006, 17, 411–424. [Google Scholar] [CrossRef] [PubMed]
- Wolf, H. The effect of hormones and vitamin B6 on urinary excretion of metabolites of the kynurenine pathway. Scand. J. Clin. Lab. Investig. Suppl. 1974, 136, 1–186. [Google Scholar]
- Guillemin, G.J.; Kerr, S.J.; Pemberton, L.A.; Smith, D.G.; Smythe, G.A.; Armati, P.J.; Brew, B.J. IFN-β1b induces kynurenine pathway metabolism in human macrophages: Potential implications for multiple sclerosis treatment. J. Interferon Cytokine Res. 2001, 21, 1097–1101. [Google Scholar] [CrossRef] [PubMed]
- Pemberton, L.A.; Kerr, S.J.; Smythe, G.; Brew, B.J. Quinolinic acid production by macrophages stimulated with IFN-γ, TNF-α, and IFN-α. J. Interferon Cytokine Res. 1997, 17, 589–595. [Google Scholar] [CrossRef] [PubMed]
- Heyes, M.P.; Chen, C.Y.; Major, E.O.; Saito, K. Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types. Biochem. J. 1997, 326 Pt 2, 351–356. [Google Scholar] [PubMed]
- 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. 2008, 441, 29–34. [Google Scholar] [CrossRef] [PubMed]
- Austin, C.J.; Rendina, L.M. Targeting key dioxygenases in tryptophan-kynurenine metabolism for immunomodulation and cancer chemotherapy. Drug Discov. Today 2014. [Google Scholar] [CrossRef]
- Sedlmayr, P. Indoleamine 2,3-dioxygenase in materno–fetal interaction. Curr. Drug MeTable 2007, 8, 205–208. [Google Scholar] [CrossRef]
- Reyes Ocampo, J.; Lugo Huitron, R.; Gonzalez-Esquivel, D.; Ugalde-Muniz, P.; Jimenez-Anguiano, A.; Pineda, B.; Pedraza-Chaverri, J.; Rios, C.; Perez de la Cruz, V. Kynurenines with neuroactive and redox properties: Relevance to aging and brain diseases. Oxid. Med. Cell. Longev. 2014. [Google Scholar] [CrossRef]
- Opitz, C.A.; Litzenburger, U.M.; Sahm, F.; Ott, M.; Tritschler, I.; Trump, S.; Schumacher, T.; Jestaedt, L.; Schrenk, D.; Weller, M.; et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 2011, 478, 197–203. [Google Scholar] [CrossRef] [Green Version]
- Denison, M.S.; Rogers, J.M.; Rushing, S.R.; Jones, C.L.; Tetangco, S.C.; Heath-Pagliuso, S. Analysis of the aryl hydrocarbon receptor (AhR) signal transduction pathway. Curr. Protoc. Toxicol. 2002. [Google Scholar] [CrossRef]
- Denison, M.S.; Nagy, S.R. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu. Rev. Pharmacol. Toxicol. 2003, 43, 309–334. [Google Scholar] [CrossRef] [PubMed]
- Kitamura, M.; Kasai, A. Cigarette smoke as a trigger for the dioxin receptor-mediated signaling pathway. Cancer Lett. 2007, 252, 184–194. [Google Scholar] [CrossRef] [PubMed]
- Mason, G.G. Dioxin-receptor ligands in urban air and vehicle exhaust. Environ. Health Perspect. 1994, 102 (Suppl. 4), 111–116. [Google Scholar] [CrossRef] [PubMed]
- Bunger, M.K.; Glover, E.; Moran, S.M.; Walisser, J.A.; Lahvis, G.P.; Hsu, E.L.; Bradfield, C.A. Abnormal liver development and resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in mice carrying a mutation in the DNA-binding domain of the aryl hydrocarbon receptor. Toxicol. Sci. 2008, 106, 83–92. [Google Scholar] [CrossRef] [PubMed]
- Julliard, W.; Fechner, J.H.; Mezrich, J.D. The aryl hydrocarbon receptor meets immunology: Friend or foe? A little of both. Front. Immunol. 2014, 5. [Google Scholar] [CrossRef]
- Vogel, C.F.; Khan, E.M.; Leung, P.S.; Gershwin, M.E.; Chang, W.L.; Wu, D.; Haarmann-Stemmann, T.; Hoffmann, A.; Denison, M.S. Cross-talk between aryl hydrocarbon receptor and the inflammatory response: A role for nuclear factor-κB. J. Biol. Chem. 2014, 289, 1866–1875. [Google Scholar] [CrossRef] [PubMed]
- Murray, I.A.; Patterson, A.D.; Perdew, G.H. Aryl hydrocarbon receptor ligands in cancer: Friend and foe. Nat. Rev. Cancer 2014, 14, 801–814. [Google Scholar] [CrossRef] [PubMed]
- DiNatale, B.C.; Murray, I.A.; Schroeder, J.C.; Flaveny, C.A.; Lahoti, T.S.; Laurenzana, E.M.; Omiecinski, C.J.; Perdew, G.H. Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling. Toxicol. Sci. 2010, 115, 89–97. [Google Scholar] [CrossRef] [PubMed]
- Gal, E.M.; Sherman, A.D. Synthesis and metabolism of l-kynurenine in rat brain. J. Neurochem. 1978, 30, 607–613. [Google Scholar] [CrossRef] [PubMed]
- Moroni, F.; Russi, P.; Lombardi, G.; Beni, M.; Carla, V. Presence of kynurenic acid in the mammalian brain. J. Neurochem. 1988, 51, 177–180. [Google Scholar] [CrossRef] [PubMed]
- Kessler, M.; Terramani, T.; Lynch, G.; Baudry, M. A glycine site associated with N-methyl-d-aspartic acid receptors: Characterization and identification of a new class of antagonists. J. Neurochem. 1989, 52, 1319–1328. [Google Scholar] [CrossRef] [PubMed]
- Danysz, W.; Fadda, E.; Wroblewski, J.T.; Costa, E. Kynurenate and 2-amino-5-phosphonovalerate interact with multiple binding sites of the N-methyl-d-aspartate-sensitive glutamate receptor domain. Neurosci. Lett. 1989, 96, 340–344. [Google Scholar] [CrossRef] [PubMed]
- Perkins, M.N.; Stone, T.W. Actions of kynurenic acid and quinolinic acid in the rat hippocampus in vivo. Exp. Neurol. 1985, 88, 570–579. [Google Scholar] [CrossRef] [PubMed]
- Prescott, C.; Weeks, A.M.; Staley, K.J.; Partin, K.M. Kynurenic acid has a dual action on AMPA receptor responses. Neurosci. Lett. 2006, 402, 108–112. [Google Scholar] [CrossRef] [PubMed]
- Rozsa, E.; Robotka, H.; Vecsei, L.; Toldi, J. The Janus-face kynurenic acid. J. Neural Transm. 2008, 115, 1087–1091. [Google Scholar] [CrossRef] [PubMed]
- Hilmas, C.; Pereira, E.F.; Alkondon, M.; Rassoulpour, A.; Schwarcz, R.; Albuquerque, E.X. The brain metabolite kynurenic acid inhibits α7 nicotinic receptor activity and increases non-α7 nicotinic receptor expression: Physiopathological implications. J. Neurosci. 2001, 21, 7463–7473. [Google Scholar] [PubMed]
- Wang, J.; Simonavicius, N.; Wu, X.; Swaminath, G.; Reagan, J.; Tian, H.; Ling, L. Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J. Biol. Chem. 2006, 281, 22021–22028. [Google Scholar] [CrossRef] [PubMed]
- Alkondon, M.; Pereira, E.F.; Todd, S.W.; Randall, W.R.; Lane, M.; Albuquerque, E.X. Functional G-protein coupled receptor 35 is expressed by neurons in the CA1 field of the hippocampus. Biochem. Pharmacol. 2014. [Google Scholar] [CrossRef]
- Ohshiro, H.; Tonai-Kachi, H.; Ichikawa, K. GPR35 is a functional receptor in rat dorsal root ganglion neurons. Biochem. Biophys. Res. Commun. 2008, 365, 344–348. [Google Scholar] [CrossRef] [PubMed]
- Lugo-Huitron, R.; Blanco-Ayala, T.; Ugalde-Muniz, P.; Carrillo-Mora, P.; Pedraza-Chaverri, J.; Silva-Adaya, D.; Maldonado, P.D.; Torres, I.; Pinzon, E.; Ortiz-Islas, E.; et al. On the antioxidant properties of kynurenic acid: Free radical scavenging activity and inhibition of oxidative stress. Neurotoxicol. Teratol. 2011, 33, 538–547. [Google Scholar] [CrossRef] [PubMed]
- Schuck, P.F.; Tonin, A.; da Costa Ferreira, G.; Viegas, C.M.; Latini, A.; Duval Wannmacher, C.M.; de Souza Wyse, A.T.; Dutra-Filho, C.S.; Wajner, M. Kynurenines impair energy metabolism in rat cerebral cortex. Cell. Mol. Neurobiol. 2007, 27, 147–160. [Google Scholar] [CrossRef] [PubMed]
- Gaubert, S.; Bouchaut, M.; Brumas, V.; Berthon, G. Copper—Ligand interactions and the physiological free radical processes. Part 3. Influence of histidine, salicylic acid and anthranilic acid on copper-driven Fenton chemistry in vitro. Free Radic. Res. 2000, 32, 451–461. [Google Scholar] [CrossRef] [PubMed]
- Miche, H.; Brumas, V.; Berthon, G. Copper(II) interactions with nonsteroidal antiinflammatory agents. II. Anthranilic acid as a potential. OH-inactivating ligand. J. Inorg. Biochem. 1997, 68, 27–38. [Google Scholar] [CrossRef] [PubMed]
- Bender, D.A.; McCreanor, G.M. The preferred route of kynurenine metabolism in the rat. Biochim. Biophys. Acta 1982, 717, 56–60. [Google Scholar] [CrossRef] [PubMed]
- Eastman, C.L.; Guilarte, T.R. The role of hydrogen peroxide in the in vitro cytotoxicity of 3-hydroxykynurenine. Neurochem. Res. 1990, 15, 1101–1107. [Google Scholar] [CrossRef]
- Ishii, T.; Iwahashi, H.; Sugata, R.; Kido, R. Formation of hydroxanthommatin-derived radical in the oxidation of 3-hydroxykynurenine. Arch. Biochem. Biophys. 1992, 294, 616–622. [Google Scholar] [CrossRef] [PubMed]
- Okuda, S.; Nishiyama, N.; Saito, H.; Katsuki, H. Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine. Proc. Natl. Acad. Sci. USA 1996, 93, 12553–12558. [Google Scholar] [CrossRef] [PubMed]
- Vazquez, S.; Garner, B.; Sheil, M.M.; Truscott, R.J. Characterisation of the major autoxidation products of 3-hydroxykynurenine under physiological conditions. Free Radic. Res. 2000, 32, 11–23. [Google Scholar] [CrossRef] [PubMed]
- Pinelli, A.; Ossi, C.; Colombo, R.; Tofanetti, O.; Spazzi, L. Experimental convulsions in rats induced by intraventricular administration of kynurenine and structurally related compounds. Neuropharmacology 1984, 23, 333–337. [Google Scholar] [CrossRef] [PubMed]
- Nakagami, Y.; Saito, H.; Katsuki, H. 3-Hydroxykynurenine toxicity on the rat striatum in vivo. Jpn. J. Pharmacol. 1996, 71, 183–186. [Google Scholar] [CrossRef] [PubMed]
- Mizdrak, J.; Hains, P.G.; Truscott, R.J.; Jamie, J.F.; Davies, M.J. Tryptophan-derived ultraviolet filter compounds covalently bound to lens proteins are photosensitizers of oxidative damage. Free Radic. Biol. Med. 2008, 44, 1108–1119. [Google Scholar] [CrossRef] [PubMed]
- Leipnitz, G.; Schumacher, C.; Dalcin, K.B.; Scussiato, K.; Solano, A.; Funchal, C.; Dutra-Filho, C.S.; Wyse, A.T.; Wannmacher, C.M.; Latini, A.; et al. In vitro evidence for an antioxidant role of 3-hydroxykynurenine and 3-hydroxyanthranilic acid in the brain. Neurochem. Int. 2007, 50, 83–94. [Google Scholar]
- Colin-Gonzalez, A.L.; Maldonado, P.D.; Santamaria, A. 3-Hydroxykynurenine: An intriguing molecule exerting dual actions in the central nervous system. Neurotoxicology 2013, 34, 189–204. [Google Scholar] [CrossRef] [PubMed]
- Dykens, J.A.; Sullivan, S.G.; Stern, A. Oxidative reactivity of the tryptophan metabolites 3-hydroxyanthranilate, cinnabarinate, quinolinate and picolinate. Biochem. Pharmacol. 1987, 36, 211–217. [Google Scholar] [CrossRef] [PubMed]
- Fazio, F.; Lionetto, L.; Molinaro, G.; Bertrand, H.O.; Acher, F.; Ngomba, R.T.; Notartomaso, S.; Curini, M.; Rosati, O.; Scarselli, P.; et al. Cinnabarinic acid, an endogenous metabolite of the kynurenine pathway, activates type 4 metabotropic glutamate receptors. Mol. Pharmacol. 2012, 81, 643–656. [Google Scholar] [CrossRef] [PubMed]
- Lowe, M.M.; Mold, J.E.; Kanwar, B.; Huang, Y.; Louie, A.; Pollastri, M.P.; Wang, C.; Patel, G.; Franks, D.G.; Schlezinger, J.; et al. Identification of cinnabarinic acid as a novel endogenous aryl hydrocarbon receptor ligand that drives IL-22 production. PLoS ONE 2014, 9, e87877. [Google Scholar] [CrossRef] [PubMed]
- Morita, T.; Saito, K.; Takemura, M.; Maekawa, N.; Fujigaki, S.; Fujii, H.; Wada, H.; Takeuchi, S.; Noma, A.; Seishima, M.; et al. 3-Hydroxyanthranilic acid, an l-tryptophan metabolite, induces apoptosis in monocyte-derived cells stimulated by interferon-gamma. Ann. Clin. Biochem. 2001, 38, 242–251. [Google Scholar] [CrossRef] [PubMed]
- Quagliariello, E.; Papa, S.; Saccone, C.; Alifano, A. Effect of 3-hydroxyanthranilic acid on the mitochondrial respiratory system. Biochem. J. 1964, 91, 137–146. [Google Scholar] [PubMed]
- Fallarino, F.; Grohmann, U.; Vacca, C.; Bianchi, R.; Orabona, C.; Spreca, A.; Fioretti, M.C.; Puccetti, P. T cell apoptosis by tryptophan catabolism. Cell Death Differ. 2002, 9, 1069–1077. [Google Scholar] [CrossRef] [PubMed]
- Christen, S.; Peterhans, E.; Stocker, R. Antioxidant activities of some tryptophan metabolites: Possible implication for inflammatory diseases. Proc. Natl. Acad. Sci. USA 1990, 87, 2506–2510. [Google Scholar] [CrossRef] [PubMed]
- Murakami, K.; Haneda, M.; Qiao, S.; Naruse, M.; Yoshino, M. Prooxidant action of rosmarinic acid: Transition metal-dependent generation of reactive oxygen species. Toxicol. In Vitro 2007, 21, 613–617. [Google Scholar] [CrossRef] [PubMed]
- Murakami, K.; Ito, M.; Yoshino, M. Xanthurenic acid inhibits metal ion-induced lipid peroxidation and protects NADP-isocitrate dehydrogenase from oxidative inactivation. J. Nutr. Sci. Vitaminol. (Tokyo) 2001, 47, 306–310. [Google Scholar] [CrossRef]
- Aggett, P.J.; Fenwick, P.K.; Kirk, H. An in vitro study of the effect of picolinic acid on metal translocation across lipid bilayers. J. Nutr. 1989, 119, 1432–1437. [Google Scholar] [PubMed]
- Beskid, M.; Jachimowicz, J.; Taraszewska, A.; Kukulska, D. Histological and ultrastructural changes in the rat brain following systemic administration of picolinic acid. Exp. Toxicol. Pathol. 1995, 47, 25–30. [Google Scholar] [CrossRef] [PubMed]
- Bosco, M.C.; Rapisarda, A.; Massazza, S.; Melillo, G.; Young, H.; Varesio, L. The tryptophan catabolite picolinic acid selectively induces the chemokines macrophage inflammatory protein-1α and -1β in macrophages. J. Immunol. 2000, 164, 3283–3291. [Google Scholar] [CrossRef] [PubMed]
- Jhamandas, K.; Boegman, R.J.; Beninger, R.J.; Bialik, M. Quinolinate-induced cortical cholinergic damage: Modulation by tryptophan metabolites. Brain Res. 1990, 529, 185–191. [Google Scholar] [CrossRef] [PubMed]
- Vrooman, L.; Jhamandas, K.; Boegman, R.J.; Beninger, R.J. Picolinic acid modulates kainic acid-evoked glutamate release from the striatum in vitro. Brain Res. 1993, 627, 193–198. [Google Scholar] [CrossRef] [PubMed]
- Braidy, N.; Grant, R.; Adams, S.; Brew, B.J.; Guillemin, G.J. Mechanism for quinolinic acid cytotoxicity in human astrocytes and neurons. Neurotox. Res. 2009, 16, 77–86. [Google Scholar] [CrossRef] [PubMed]
- Stone, T.W.; Perkins, M.N. Quinolinic acid: A potent endogenous excitant at amino acid receptors in CNS. Eur. J. Pharmacol. 1981, 72, 411–412. [Google Scholar] [CrossRef] [PubMed]
- De Carvalho, L.P.; Bochet, P.; Rossier, J. The endogenous agonist quinolinic acid and the non endogenous homoquinolinic acid discriminate between NMDAR2 receptor subunits. Neurochem. Int. 1996, 28, 445–452. [Google Scholar]
- Schwarcz, R.; Kohler, C. Differential vulnerability of central neurons of the rat to quinolinic acid. Neurosci. Lett. 1983, 38, 85–90. [Google Scholar] [CrossRef]
- Tavares, R.G.; Tasca, C.I.; Santos, C.E.; Alves, L.B.; Porciuncula, L.O.; Emanuelli, T.; Souza, D.O. Quinolinic acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes. Neurochem. Int. 2002, 40, 621–627. [Google Scholar] [CrossRef] [PubMed]
- Rios, C.; Santamaria, A. Quinolinic acid is a potent lipid peroxidant in rat brain homogenates. Neurochem. Res. 1991, 16, 1139–1143. [Google Scholar] [CrossRef] [PubMed]
- Goda, K.; Kishimoto, R.; Shimizu, S.; Hamane, Y.; Ueda, M. Quinolinic acid and active oxygens. Possible contribution of active oxygens during cell death in the brain. Adv. Exp. Med. Biol. 1996, 398, 247–254. [Google Scholar] [PubMed]
- Stipek, S.; Stastny, F.; Platenik, J.; Crkovska, J.; Zima, T. The effect of quinolinate on rat brain lipid peroxidation is dependent on iron. Neurochem. Int. 1997, 30, 233–237. [Google Scholar] [CrossRef] [PubMed]
- Chen, Y.; Brew, B.J.; Guillemin, G.J. Characterization of the kynurenine pathway in NSC-34 cell line: Implications for amyotrophic lateral sclerosis. J. Neurochem. 2011, 118, 816–825. [Google Scholar] [CrossRef] [PubMed]
- Espey, M.G.; Chernyshev, O.N.; Reinhard, J.F., Jr.; Namboodiri, M.A.; Colton, C.A. Activated human microglia produce the excitotoxin quinolinic acid. Neuroreport 1997, 8, 431–434. [Google Scholar] [CrossRef] [PubMed]
- Guillemin, G.J.; Kerr, S.J.; Smythe, G.A.; Smith, D.G.; Kapoor, V.; Armati, P.J.; Croitoru, J.; Brew, B.J. Kynurenine pathway metabolism in human astrocytes: A paradox for neuronal protection. J. Neurochem. 2001, 78, 842–853. [Google Scholar] [CrossRef] [PubMed]
- Heyes, M.P.; Achim, C.L.; Wiley, C.A.; Major, E.O.; Saito, K.; Markey, S.P. Human microglia convert l-tryptophan into the neurotoxin quinolinic acid. Biochem. J. 1996, 320 Pt 2, 595–597. [Google Scholar] [PubMed]
- Rzeski, W.; Kocki, T.; Dybel, A.; Wejksza, K.; Zdzisinska, B.; Kandefer-Szerszen, M.; Turski, W.A.; Okuno, E.; Albrecht, J. Demonstration of kynurenine aminotransferases I and II and characterization of kynurenic acid synthesis in cultured cerebral cortical neurons. J. Neurosci. Res. 2005, 80, 677–682. [Google Scholar] [CrossRef] [PubMed]
- Guillemin, G.J.; Cullen, K.M.; Lim, C.K.; Smythe, G.A.; Garner, B.; Kapoor, V.; Takikawa, O.; Brew, B.J. Characterization of the kynurenine pathway in human neurons. J. Neurosci. 2007, 27, 12884–12892. [Google Scholar] [CrossRef] [PubMed]
- Widner, B.; Leblhuber, F.; Walli, J.; Tilz, G.P.; Demel, U.; Fuchs, D. Tryptophan degradation and immune activation in Alzheimer’s disease. J. Neural Transm. 2000, 107, 343–353. [Google Scholar] [CrossRef] [PubMed]
- Schwarz, M.J.; Guillemin, G.J.; Teipel, S.J.; Buerger, K.; Hampel, H. Increased 3-hydroxykynurenine serum concentrations differentiate Alzheimer’s disease patients from controls. Eur. Arch. Psychiatry Clin. Neurosci. 2013, 263, 345–352. [Google Scholar] [CrossRef] [PubMed]
- 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. 2005, 31, 395–404. [Google Scholar] [CrossRef] [PubMed]
- Rahman, A.; Ting, K.; Cullen, K.M.; Braidy, N.; Brew, B.J.; Guillemin, G.J. The excitotoxin quinolinic acid induces tau phosphorylation in human neurons. PLoS ONE 2009, 4, e6344. [Google Scholar] [CrossRef] [PubMed]
- Baran, H.; Jellinger, K.; Deecke, L. Kynurenine metabolism in Alzheimer’s disease. J. Neural Transm. 1999, 106, 165–181. [Google Scholar] [CrossRef] [PubMed]
- Braak, H.; del Tredici, K.; Rub, U.; de Vos, R.A.; Jansen Steur, E.N.; Braak, E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 2003, 24, 197–211. [Google Scholar] [CrossRef] [PubMed]
- Lin, M.T.; Beal, M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006, 443, 787–795. [Google Scholar] [CrossRef] [PubMed]
- Zadori, D.; Szalardy, L.; Toldi, J.; Fulop, F.; Klivenyi, P.; Vecsei, L. Some molecular mechanisms of dopaminergic and glutamatergic dysfunctioning in Parkinson’s disease. J. Neural Transm. 2013, 120, 673–681. [Google Scholar] [CrossRef] [PubMed]
- Widner, B.; Leblhuber, F.; Fuchs, D. Increased neopterin production and tryptophan degradation in advanced Parkinson’s disease. J. Neural Transm. 2002, 109, 181–189. [Google Scholar] [CrossRef] [PubMed]
- Ogawa, T.; Matson, W.R.; Beal, M.F.; Myers, R.H.; Bird, E.D.; Milbury, P.; Saso, S. Kynurenine pathway abnormalities in Parkinson’s disease. Neurology 1992, 42, 1702–1706. [Google Scholar] [CrossRef] [PubMed]
- Lewitt, P.A.; Li, J.; Lu, M.; Beach, T.G.; Adler, C.H.; Guo, L. 3-hydroxykynurenine and other Parkinson’s disease biomarkers discovered by metabolomic analysis. Mov. Disord. 2013, 28, 1653–1660. [Google Scholar] [CrossRef] [PubMed]
- Beal, M.F.; Kowall, N.W.; Ellison, D.W.; Mazurek, M.F.; Swartz, K.J.; Martin, J.B. Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature 1986, 321, 168–171. [Google Scholar] [CrossRef] [PubMed]
- Heyes, M.P.; Swartz, K.J.; Markey, S.P.; Beal, M.F. Regional brain and cerebrospinal fluid quinolinic acid concentrations in Huntington’s disease. Neurosci. Lett. 1991, 122, 265–269. [Google Scholar] [CrossRef]
- Beal, M.F.; Matson, W.R.; Storey, E.; Milbury, P.; Ryan, E.A.; Ogawa, T.; Bird, E.D. Kynurenic acid concentrations are reduced in Huntington’s disease cerebral cortex. J. Neurol. Sci. 1992, 108, 80–87. [Google Scholar] [CrossRef] [PubMed]
- Beal, M.F.; Matson, W.R.; Swartz, K.J.; Gamache, P.H.; Bird, E.D. Kynurenine pathway measurements in Huntington’s disease striatum: Evidence for reduced formation of kynurenic acid. J. Neurochem. 1990, 55, 1327–1339. [Google Scholar] [CrossRef] [PubMed]
- Heyes, M.P.; Saito, K.; Crowley, J.S.; Davis, L.E.; Demitrack, M.A.; Der, M.; Dilling, L.A.; Elia, J.; Kruesi, M.J.; Lackner, A.; et al. Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. Brain 1992, 115 Pt 5, 1249–1273. [Google Scholar] [CrossRef] [PubMed]
- Jauch, D.; Urbanska, E.M.; Guidetti, P.; Bird, E.D.; Vonsattel, J.P.; Whetsell, W.O., Jr.; Schwarcz, R. Dysfunction of brain kynurenic acid metabolism in Huntington’s disease: Focus on kynurenine aminotransferases. J. Neurol. Sci. 1995, 130, 39–47. [Google Scholar] [CrossRef] [PubMed]
- Pearson, S.J.; Reynolds, G.P. Increased brain concentrations of a neurotoxin, 3-hydroxykynurenine, in Huntington’s disease. Neurosci. Lett. 1992, 144, 199–201. [Google Scholar] [CrossRef] [PubMed]
- 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. 2004, 17, 455–461. [Google Scholar] [CrossRef] [PubMed]
- Rosen, D.R. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993, 364, 362. [Google Scholar] [PubMed]
- Chen, Y.; Stankovic, R.; Cullen, K.M.; Meininger, V.; Garner, B.; Coggan, S.; Grant, R.; Brew, B.J.; Guillemin, G.J. The kynurenine pathway and inflammation in amyotrophic lateral sclerosis. Neurotox. Res. 2010, 18, 132–142. [Google Scholar] [CrossRef] [PubMed]
- Ilzecka, J.; Kocki, T.; Stelmasiak, Z.; Turski, W.A. Endogenous protectant kynurenic acid in amyotrophic lateral sclerosis. Acta Neurol. Scand. 2003, 107, 412–418. [Google Scholar] [CrossRef] [PubMed]
- Monaco, F.; Fumero, S.; Mondino, A.; Mutani, R. Plasma and cerebrospinal fluid tryptophan in multiple sclerosis and degenerative diseases. J. Neurol. Neurosurg. Psychiatry 1979, 42, 640–641. [Google Scholar] [CrossRef] [PubMed]
- Ott, M.; Demisch, L.; Engelhardt, W.; Fischer, P.A. Interleukin-2, soluble interleukin-2-receptor, neopterin, l-tryptophan and β2-microglobulin levels in CSF and serum of patients with relapsing-remitting or chronic-progressive multiple sclerosis. J. Neurol. 1993, 241, 108–114. [Google Scholar] [CrossRef] [PubMed]
- Hartai, Z.; Klivenyi, P.; Janaky, T.; Penke, B.; Dux, L.; Vecsei, L. Kynurenine metabolism in multiple sclerosis. Acta Neurol. Scand. 2005, 112, 93–96. [Google Scholar] [CrossRef] [PubMed]
- Rejdak, K.; Bartosik-Psujek, H.; Dobosz, B.; Kocki, T.; Grieb, P.; Giovannoni, G.; Turski, W.A.; Stelmasiak, Z. Decreased level of kynurenic acid in cerebrospinal fluid of relapsing-onset multiple sclerosis patients. Neurosci. Lett. 2002, 331, 63–65. [Google Scholar] [CrossRef] [PubMed]
- Rejdak, K.; Petzold, A.; Kocki, T.; Kurzepa, J.; Grieb, P.; Turski, W.A.; Stelmasiak, Z. Astrocytic activation in relation to inflammatory markers during clinical exacerbation of relapsing-remitting multiple sclerosis. J. Neural Transm. 2007, 114, 1011–1015. [Google Scholar] [CrossRef] [PubMed]
- Amirkhani, A.; Rajda, C.; Arvidsson, B.; Bencsik, K.; Boda, K.; Seres, E.; Markides, K.E.; Vecsei, L.; Bergquist, J. Interferon-β affects the tryptophan metabolism in multiple sclerosis patients. Eur. J. Neurol. 2005, 12, 625–631. [Google Scholar] [CrossRef] [PubMed]
- Durastanti, V.; Lugaresi, A.; Bramanti, P.; Amato, M.; Bellantonio, P.; de Luca, G.; Picconi, O.; Fantozzi, R.; Locatelli, L.; Solda, A.; et al. Neopterin production and tryptophan degradation during 24-months therapy with interferon β-1a in multiple sclerosis patients. J. Transl. Med. 2011, 9. [Google Scholar] [CrossRef] [PubMed]
- Mandi, Y.; Vecsei, L. The kynurenine system and immunoregulation. J. Neural Transm. 2012, 119, 197–209. [Google Scholar] [CrossRef] [PubMed]
- Heaton, R.K.; Clifford, D.B.; Franklin, D.R., Jr.; Woods, S.P.; Ake, C.; Vaida, F.; Ellis, R.J.; Letendre, S.L.; Marcotte, T.D.; Atkinson, J.H.; et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: Charter Study. Neurology 2010, 75, 2087–2096. [Google Scholar] [CrossRef] [PubMed]
- Heyes, M.P.; Brew, B.J.; Martin, A.; Price, R.W.; Salazar, A.M.; Sidtis, J.J.; Yergey, J.A.; Mouradian, M.M.; Sadler, A.E.; Keilp, J.; et al. Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infection: Relationship to clinical and neurological status. Ann. Neurol. 1991, 29, 202–209. [Google Scholar] [CrossRef] [PubMed]
- Guillemin, G.J.; Kerr, S.J.; Brew, B.J. Involvement of quinolinic acid in AIDS dementia complex. Neurotox. Res. 2005, 7, 103–123. [Google Scholar] [CrossRef] [PubMed]
- Chiarugi, A.; Carpenedo, R.; Molina, M.T.; Mattoli, L.; Pellicciari, R.; Moroni, F. Comparison of the neurochemical and behavioral effects resulting from the inhibition of kynurenine hydroxylase and/or kynureninase. J. Neurochem. 1995, 65, 1176–1183. [Google Scholar] [CrossRef] [PubMed]
- Colabroy, K.L.; Zhai, H.; Li, T.; Ge, Y.; Zhang, Y.; Liu, A.; Ealick, S.E.; McLafferty, F.W.; Begley, T.P. The mechanism of inactivation of 3-hydroxyanthranilate-3,4-dioxygenase by 4-chloro-3-hydroxyanthranilate. Biochemistry 2005, 44, 7623–7631. [Google Scholar] [CrossRef] [PubMed]
- Walsh, H.A.; O’Shea, K.C.; Botting, N.P. Comparative inhibition by substrate analogues 3-methoxy- and 3-hydroxydesaminokynurenine and an improved 3 step purification of recombinant human kynureninase. BMC Biochem. 2003, 4. [Google Scholar] [CrossRef] [Green Version]
- 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. 2009, 109, 316–325. [Google Scholar] [CrossRef] [PubMed]
- Gregoire, L.; Rassoulpour, A.; Guidetti, P.; Samadi, P.; Bedard, P.J.; Izzo, E.; Schwarcz, R.; di Paolo, T. Prolonged kynurenine 3-hydroxylase inhibition reduces development of levodopa-induced dyskinesias in parkinsonian monkeys. Behav. Brain Res. 2008, 186, 161–167. [Google Scholar] [CrossRef] [PubMed]
- Samadi, P.; Gregoire, L.; Rassoulpour, A.; Guidetti, P.; Izzo, E.; Schwarcz, R.; Bedard, P.J. Effect of kynurenine 3-hydroxylase inhibition on the dyskinetic and antiparkinsonian responses to levodopa in Parkinsonian monkeys. Mov. Disord. 2005, 20, 792–802. [Google Scholar] [CrossRef] [PubMed]
- Zwilling, D.; Huang, S.Y.; Sathyasaikumar, K.V.; Notarangelo, F.M.; Guidetti, P.; Wu, H.Q.; Lee, J.; Truong, J.; Andrews-Zwilling, Y.; Hsieh, E.W.; et al. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell 2011, 145, 863–874. [Google Scholar] [CrossRef] [PubMed]
- Beconi, M.G.; Yates, D.; Lyons, K.; Matthews, K.; Clifton, S.; Mead, T.; Prime, M.; Winkler, D.; O’Connell, C.; Walter, D.; et al. Metabolism and pharmacokinetics of JM6 in mice: JM6 is not a prodrug for Ro-61-8048. Drug Metab. Dispos. 2012, 40, 2297–2306. [Google Scholar] [CrossRef] [PubMed]
- Chauvel, V.; Vamos, E.; Pardutz, A.; Vecsei, L.; Schoenen, J.; Multon, S. Effect of systemic kynurenine on cortical spreading depression and its modulation by sex hormones in rat. Exp. Neurol. 2012, 236, 207–214. [Google Scholar] [CrossRef] [PubMed]
- Silva-Adaya, D.; Perez-de la Cruz, V.; Villeda-Hernandez, J.; Carrillo-Mora, P.; Gonzalez-Herrera, I.G.; Garcia, E.; Colin-Barenque, L.; Pedraza-Chaverri, J.; Santamaria, A. Protective effect of l-kynurenine and probenecid on 6-hydroxydopamine-induced striatal toxicity in rats: Implications of modulating kynurenate as a protective strategy. Neurotoxicol. Teratol. 2011, 33, 303–312. [Google Scholar] [CrossRef] [PubMed]
- Carrillo-Mora, P.; Mendez-Cuesta, L.A.; Perez-de la Cruz, V.; Fortoul-van der Goes, T.I.; Santamaria, A. Protective effect of systemic l-kynurenine and probenecid administration on behavioural and morphological alterations induced by toxic soluble amyloid β(25–35) in rat hippocampus. Behav. Brain Res. 2010, 210, 240–250. [Google Scholar] [CrossRef] [PubMed]
- Robotka, H.; Sas, K.; Agoston, M.; Rozsa, E.; Szenasi, G.; Gigler, G.; Vecsei, L.; Toldi, J. Neuroprotection achieved in the ischaemic rat cortex with l-kynurenine sulphate. Life Sci. 2008, 82, 915–919. [Google Scholar] [CrossRef] [PubMed]
- Sas, K.; Robotka, H.; Rozsa, E.; Agoston, M.; Szenasi, G.; Gigler, G.; Marosi, M.; Kis, Z.; Farkas, T.; Vecsei, L.; et al. Kynurenine diminishes the ischemia-induced histological and electrophysiological deficits in the rat hippocampus. Neurobiol. Dis. 2008, 32, 302–308. [Google Scholar] [CrossRef] [PubMed]
- Miranda, A.F.; Sutton, M.A.; Beninger, R.J.; Jhamandas, K.; Boegman, R.J. Quinolinic acid lesion of the nigrostriatal pathway: Effect on turning behaviour and protection by elevation of endogenous kynurenic acid in Rattus norvegicus. Neurosci. Lett. 1999, 262, 81–84. [Google Scholar] [CrossRef] [PubMed]
- Marosi, M.; Nagy, D.; Farkas, T.; Kis, Z.; Rozsa, E.; Robotka, H.; Fulop, F.; Vecsei, L.; Toldi, J. A novel kynurenic acid analogue: A comparison with kynurenic acid. An in vitro electrophysiological study. J. Neural Transm. 2010, 117, 183–188. [Google Scholar] [CrossRef] [PubMed]
- Zadori, D.; Nyiri, G.; Szonyi, A.; Szatmari, I.; Fulop, F.; Toldi, J.; Freund, T.F.; Vecsei, L.; Klivenyi, P. Neuroprotective effects of a novel kynurenic acid analogue in a transgenic mouse model of Huntington’s disease. J. Neural Transm. 2011, 118, 865–875. [Google Scholar] [CrossRef] [PubMed]
- Tiszlavicz, Z.; Nemeth, B.; Fulop, F.; Vecsei, L.; Tapai, K.; Ocsovszky, I.; Mandi, Y. Different inhibitory effects of kynurenic acid and a novel kynurenic acid analogue on tumour necrosis factor-alpha (TNF-α) production by mononuclear cells, HMGB1 production by monocytes and HNP1-3 secretion by neutrophils. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2011, 383, 447–455. [Google Scholar] [CrossRef]
- Gellert, L.; Fuzik, J.; Goblos, A.; Sarkozi, K.; Marosi, M.; Kis, Z.; Farkas, T.; Szatmari, I.; Fulop, F.; Vecsei, L.; et al. Neuroprotection with a new kynurenic acid analog in the four-vessel occlusion model of ischemia. Eur. J. Pharmacol. 2011, 667, 182–187. [Google Scholar] [CrossRef] [PubMed]
- Gellert, L.; Varga, D.; Ruszka, M.; Toldi, J.; Farkas, T.; Szatmari, I.; Fulop, F.; Vecsei, L.; Kis, Z. Behavioural studies with a newly developed neuroprotective KYNA-amide. J. Neural Transm. 2012, 119, 165–172. [Google Scholar] [CrossRef] [PubMed]
- Fulop, F.; Szatmari, I.; Vamos, E.; Zadori, D.; Toldi, J.; Vecsei, L. Syntheses, transformations and pharmaceutical applications of kynurenic acid derivatives. Curr. Med. Chem. 2009, 16, 4828–4842. [Google Scholar] [CrossRef] [PubMed]
- Fulop, F.; Szatmari, I.; Toldi, J.; Vecsei, L. Modifications on the carboxylic function of kynurenic acid. J. Neural Transm. 2012, 119, 109–114. [Google Scholar] [CrossRef] [PubMed]
- Kemp, J.A.; Foster, A.C.; Leeson, P.D.; Priestley, T.; Tridgett, R.; Iversen, L.L.; Woodruff, G.N. 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-d-aspartate receptor complex. Proc. Natl. Acad. Sci. USA 1988, 85, 6547–6550. [Google Scholar] [CrossRef] [PubMed]
- Domenici, M.R.; Longo, R.; Sagratella, S. 7-Chlorokynurenic acid prevents in vitro epileptiform and neurotoxic effects due to kainic acid. Gen. Pharmacol. 1996, 27, 113–116. [Google Scholar] [CrossRef] [PubMed]
- Wu, H.Q.; Lee, S.C.; Schwarcz, R. Systemic administration of 4-chlorokynurenine prevents quinolinate neurotoxicity in the rat hippocampus. Eur. J. Pharmacol. 2000, 390, 267–274. [Google Scholar] [CrossRef] [PubMed]
© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Bohár, Z.; Toldi, J.; Fülöp, F.; Vécsei, L. Changing the Face of Kynurenines and Neurotoxicity: Therapeutic Considerations. Int. J. Mol. Sci. 2015, 16, 9772-9793. https://doi.org/10.3390/ijms16059772
Bohár Z, Toldi J, Fülöp F, Vécsei L. Changing the Face of Kynurenines and Neurotoxicity: Therapeutic Considerations. International Journal of Molecular Sciences. 2015; 16(5):9772-9793. https://doi.org/10.3390/ijms16059772
Chicago/Turabian StyleBohár, Zsuzsanna, József Toldi, Ferenc Fülöp, and László Vécsei. 2015. "Changing the Face of Kynurenines and Neurotoxicity: Therapeutic Considerations" International Journal of Molecular Sciences 16, no. 5: 9772-9793. https://doi.org/10.3390/ijms16059772