Quinolinic acid (QUIN), a neuroactive metabolite of the kynurenine pathway, is normally presented in nanomolar concentrations in human brain and cerebrospinal fluid (CSF) and is often implicated in the pathogenesis of a variety of human neurological diseases. QUIN is an agonist of N-methyl-D-aspartate (NMDA) receptor, and it has a high in vivo potency as an excitotoxin. In fact, although QUIN has an uptake system, its neuronal degradation enzyme is rapidly saturated, and the rest of extracellular QUIN can continue stimulating the NMDA receptor. However, its toxicity cannot be fully explained by its activation of NMDA receptors it is likely that additional mechanisms may also be involved. In this review we describe some of the most relevant targets of QUIN neurotoxicity which involves presynaptic receptors, energetic dysfunction, oxidative stress, transcription factors, cytoskeletal disruption, behavior alterations, and cell death. 1. Biosynthesis of Quinolinic Acid (QUIN) Tryptophan (TRP) is an essential amino acid that has various important biological functions. In mammals, about 90% of dietary TRP is metabolized along the kynurenine pathway (KP) (Figure 1) [1, 2], which represents the major catabolic route of TRP and a source of nicotinamide adenine nucleotide (NAD+), a cofactor in cellular respiration and energy production that plays an important role in the DNA repair and transcriptional regulation [3, 4]. In recent years, the KP has been studied given that it contains metabolites with neuroactive and redox properties. An imbalance in the levels of some metabolites of this pathway has been involved in different pathologies. Figure 1: Kynurenine pathway. NAD += nicotinamide adenine dinucleotide. The first regulatory step of the KP is the oxidative cleavage of the TRP by tryptophan 2,3-dioxygenase and indolamine 2,3-dioxygenases 1 and 2 (IDO-1 and IDO-2). The product of this cleavage is formylkynurenine, which is hydrolyzed by a formamidase enzyme to give kynurenine (KYN). This metabolite is at a branch point in the pathway and can be further metabolized by three different enzymes: (1) kynureninase, which catalyzes the conversion of KYN to anthranilic acid (AA), (2) kynurenine aminotransferases I, II and III, which catalyze the transamination of KYN to form kynurenic acid (KYNA), and (3) kynurenine 3-hydroxylase, which produces 3-hydroxykynurenine (3-HK) from L-KYN. This branch is the most important route for QUIN synthesis, and it is known that this enzyme has the highest affinity for L-KYN, suggesting that under normal conditions, it metabolizes
References
[1]
L. Musajo and C. A. Benassi, “Aspects of disorders of the Kynurenine pathway of Tryptophan metabolism in man,” Advances in Clinical Chemistry, vol. 7, pp. 63–135, 1964.
[2]
H. Wolf, “The effect of hormones and vitamin B6 on urinary excretion of metabolites of the kynurenine pathway,” Scandinavian Journal of Clinical and Laboratory Investigation, vol. 136, pp. 1–186, 1974.
[3]
R. M. Anderson, K. J. Bitterman, J. G. Wood et al., “Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels,” The Journal of Biological Chemistry, vol. 277, no. 21, pp. 18881–18890, 2002.
[4]
H. Massudi, R. Grant, G. J. Guillemin, and N. Braidy, “NAD+ metabolism and oxidative stress: the golden nucleotide on a crown of thorns,” Redox Report, vol. 17, no. 1, pp. 28–46, 2012.
[5]
D. A. Bender and G. M. McCreanor, “The preferred route of kynurenine metabolism in the rat,” Biochimica et Biophysica Acta, vol. 717, no. 1, pp. 56–60, 1982.
[6]
A. C. Foster, R. J. White, and R. Schwarcz, “Synthesis of quinolinic acid by 3-hydroxyanthranilic acid oxygenase in rat brain tissue in vitro,” Journal of Neurochemistry, vol. 47, no. 1, pp. 23–30, 1986.
[7]
N. Braidy, R. Grant, B. J. Brew, S. Adams, T. Jayasena, and G. J. Guillemin, “Effects of kynurenine pathway metabolites on intracellular NAD+ synthesis and cell death in human primary astrocytes and neurons,” International Journal of Tryptophan Research, vol. 2, no. 1, pp. 61–69, 2009.
[8]
T. W. Stone, “Neuropharmacology of quinolinic and kynurenic acids,” Pharmacological Reviews, vol. 45, no. 3, pp. 309–379, 1993.
[9]
R. C. Roberts, K. E. McCarthy, F. Du, P. Ottersen, E. Okuno, and R. Schwarcz, “3-Hydroxyanthranilic acid oxygenase-containing astrocytic processes surround glutamate-containing axon terminals in the rat striatum,” The Journal of Neuroscience, vol. 15, no. 2, pp. 1150–1161, 1995.
[10]
A. C. Foster, W. O. Whetsell Jr., E. D. Bird, and R. Schwarcz, “Quinolinic acid phosphoribosyltransferase in human and rat brain: activity in Huntington's disease and in quinolinate-lesioned rat striatum,” Brain Research, vol. 336, no. 2, pp. 207–214, 1985.
[11]
A. C. Foster, W. C. Zinkand, and R. Schwarcz, “Quinolinic acid phosphoribosyltransferase in rat brain,” Journal of Neurochemistry, vol. 44, no. 2, pp. 446–454, 1985.
[12]
H. G. McDaniel, W. J. Reddy, and B. R. Boshell, “The mechanism of inhibition of phosphoenolpyruvate carboxylase by quinolinic acid,” Biochimica et Biophysica Acta, vol. 276, no. 2, pp. 543–550, 1972.
[13]
M. P. Heyes, C. L. Achim, C. A. Wiley, E. O. Major, K. Saito, and S. P. Markey, “Human microglia convert L-tryptophan into the neurotoxin quinolinic acid,” The Biochemical Journal, vol. 320, no. 2, pp. 595–597, 1996.
[14]
G. J. Guillemin, D. G. Smith, G. A. Smythe, P. J. Armati, and B. J. Brew, “Expression of the kynurenine pathway enzymes in human microglia and macrophages,” Advances in Experimental Medicine and Biology, vol. 527, pp. 105–112, 2003.
[15]
G. J. Guillemin, G. Smythe, O. Takikawa, and B. J. Brew, “Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons,” GLIA, vol. 49, no. 1, pp. 15–23, 2005.
[16]
F. Moroni, G. Lombardi, V. Carla, and G. Moneti, “The excitotoxin quinolinic acid is present and unevenly distributed in the rat brain,” Brain Research, vol. 295, no. 2, pp. 352–355, 1984.
[17]
F. Moroni, G. Lombardi, G. Moneti, and C. Aldinio, “The excitotoxin quinolinic acid is present in the brain of several mammals and its cortical content increases during the aging process,” Neuroscience Letters, vol. 47, no. 1, pp. 51–55, 1984.
[18]
Y. Chen and G. J. Guillemin, “Kynurenine pathway metabolites in humans: disease and healthy states,” International Journal of Tryptophan Research, vol. 2, no. 1, pp. 1–19, 2009.
[19]
A. C. Foster, L. P. Miller, W. H. Oldendorf, and R. Schwarcz, “Studies on the disposition of quinolinic acid after intracerebral or systemic administration in the rat,” Experimental Neurology, vol. 84, no. 2, pp. 428–440, 1984.
[20]
C. Kohler, L. G. Eriksson, P. R. Flood, J. A. Hardie, E. Okuno, and R. Schwarcz, “Quinolinic acid metabolism in the rat brain. Immunohistochemical identification of 3-hydroxyanthranilic acid oxygenase and quinolinic acid phosphoribosyltransferase in the hippocampal region,” The Journal of Neuroscience, vol. 8, no. 3, pp. 975–987, 1988.
[21]
A. C. Foster, E. Okuno, D. S. Brougher, and R. Schwarcz, “A radioenzymatic assay for quinolinic acid,” Analytical Biochemistry, vol. 158, no. 1, pp. 98–103, 1986.
[22]
A. C. Müller, A. Dairam, J. L. Limson, and S. Daya, “Mechanisms by which acyclovir reduces the oxidative neurotoxicity and biosynthesis of quinolinic acid,” Life Sciences, vol. 80, no. 10, pp. 918–925, 2007.
[23]
E. K. Stachowski and R. Schwarcz, “Regulation of quinolinic acid neosynthesis in mouse, rat and human brain by iron and iron chelators in vitro,” Journal of Neural Transmission, vol. 119, no. 2, pp. 123–131, 2012.
[24]
G. J. Guillemin, “Quinolinic acid: neurotoxicity,” The FEBS Journal, vol. 279, no. 8, p. 1355, 2012.
[25]
A. Rahman, K. Ting, K. M. Cullen, N. Braidy, B. J. Brew, and G. J. Guillemin, “The excitotoxin quinolinic acid induces tau phosphorylation in human neurons,” PLoS ONE, vol. 4, no. 7, Article ID e6344, 2009.
[26]
G. J. Guillemin, B. J. Brew, C. E. Noonan, O. Takikawa, and K. M. Cullen, “Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer's disease hippocampus,” Neuropathology and Applied Neurobiology, vol. 31, no. 4, pp. 395–404, 2005.
[27]
T. W. Stone and J. H. Connick, “Quinolinic acid and other kynurenines in the central nervous system,” Neuroscience, vol. 15, no. 3, pp. 597–617, 1985.
[28]
I. P. Lapin, “Stimulant and convulsive effects of kynurenines injected into brain ventricles in mice,” Journal of Neural Transmission, vol. 42, no. 1, pp. 37–43, 1978.
[29]
T. W. Stone and M. N. Perkins, “Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS,” European Journal of Pharmacology, vol. 72, no. 4, pp. 411–412, 1981.
[30]
R. Schwarcz, W. O. Whetsell Jr., and R. M. Mangano, “Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain,” Science, vol. 219, no. 4582, pp. 316–318, 1983.
[31]
L. Prado de Carvalho, P. Bochet, and J. Rossier, “The endogenous agonist quinolinic acid and the non endogenous homoquinolinic acid discriminate between NMDAR2 receptor subunits,” Neurochemistry International, vol. 28, no. 4, pp. 445–452, 1996.
[32]
R. Schwarcz and C. Kohler, “Differential vulnerability of central neurons of the rat to quinolinic acid,” Neuroscience Letters, vol. 38, no. 1, pp. 85–90, 1983.
[33]
S. Nakanishi, “Molecular diversity of glutamate receptors and implications for brain function,” Science, vol. 258, no. 5082, pp. 597–603, 1992.
[34]
A. C. Foster, J. F. Collins, and R. Schwarcz, “On the excitotoxic properties of quinolinic acid, 2,3-piperidine dicarboxylic acids and structurally related compounds,” Neuropharmacology, vol. 22, no. 12, pp. 1331–1342, 1983.
[35]
M. F. Beal, N. W. Kowall, D. W. Ellison, M. F. Mazurek, K. J. Swartz, and J. B. Martin, “Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid,” Nature, vol. 321, no. 6066, pp. 168–171, 1986.
[36]
R. G. Tavares, C. I. Tasca, C. E. S. Santos, M. Wajner, D. O. Souza, and C. S. Dutra-Filho, “Quinolinic acid inhibits glutamate uptake into synaptic vesicles from rat brain,” NeuroReport, vol. 11, no. 2, pp. 249–253, 2000.
[37]
R. G. Tavares, C. I. Tasca, C. E. S. Santos et al., “Quinolinic acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes,” Neurochemistry International, vol. 40, no. 7, pp. 621–627, 2002.
[38]
G. Baverel, G. Martin, and C. Michoudet, “Glutamine synthesis from aspartate in guinea-pig renal cortex,” The Biochemical Journal, vol. 268, no. 2, pp. 437–442, 1990.
[39]
K. K. Ting, B. J. Brew, and G. J. Guillemin, “Effect of quinolinic acid on human astrocytes morphology and functions: implications in Alzheimer's disease,” Journal of Neuroinflammation, vol. 6, article 36, 2009.
[40]
G. J. Guillemin, K. M. Cullen, C. K. Lim et al., “Characterization of the kynurenine pathway in human neurons,” The Journal of Neuroscience, vol. 27, no. 47, pp. 12884–12892, 2007.
[41]
Y. Sei, L. Fossom, G. Goping, P. Skolnick, and A. S. Basile, “Quinolinic acid protects rat cerebellar granule cells from glutamate- induced apoptosis,” Neuroscience Letters, vol. 241, no. 2-3, pp. 180–184, 1998.
[42]
W. O. Whetsell Jr. and R. Schwarcz, “Prolonged exposure to submicromolar concentrations of quinolinic acid causes excitotoxic damage in organotypic cultures of rat corticostriatal system,” Neuroscience Letters, vol. 97, no. 3, pp. 271–275, 1989.
[43]
S. J. Kerr, P. J. Armati, G. J. Guillemin, and B. J. Brew, “Chronic exposure of human neurons to quinolinic acid results in neuronal changes consistent with AIDS dementia complex,” AIDS, vol. 12, no. 4, pp. 355–363, 1998.
[44]
P. Pierozan, A. Zamoner, ？. Krombauer Soska et al., “Acute intrastriatal administration of quinolinic acid provokes hyperphosphorylation of cytoskeletal intermediate filament proteins in astrocytes and neurons of rats,” Experimental Neurology, vol. 224, no. 1, pp. 188–196, 2010.
[45]
P. Pierozan, A. Zamoner, ？. K. Soska et al., “Signaling mechanisms downstream of quinolinic acid targeting the cytoskeleton of rat striatal neurons and astrocytes,” Experimental Neurology, vol. 233, no. 1, pp. 391–399, 2012.
[46]
A. M. A. P. Fernandes, A. M. Landeira-Fernandez, P. Souza-Santos, P. C. Carvalho-Alves, and R. F. Castilho, “Quinolinate-induced rat striatal excitotoxicity impairs endoplasmic reticulum Ca2+-ATPase function,” Neurochemical Research, vol. 33, no. 9, pp. 1749–1758, 2008.
[47]
M. Naoi, R. Ishiki, Y. Nomura, S. Hasegawa, and T. Nagatsu, “Quinolinic acid: an endogenous inhibitor specific for type B monoamine oxidase in human brain synaptosomes,” Neuroscience Letters, vol. 74, no. 2, pp. 232–236, 1987.
[48]
Y. M. Bordelon, M.-F. Chesselet, D. Nelson, F. Welsh, and M. Erecińska, “Energetic dysfunction in quinolinic acid-lesioned rat striatum,” Journal of Neurochemistry, vol. 69, no. 4, pp. 1629–1639, 1997.
[49]
Y. M. Bordelon, M.-F. Chesselet, M. Erecińska, and I. A. Silver, “Effects of intrastriatal injection of quinolinic acid on electrical activity and extracellular ion concentrations in rat striatum in vivo,” Neuroscience, vol. 83, no. 2, pp. 459–469, 1998.
[50]
F. Pérez-Severiano, B. Escalante, and C. Ríos, “Nitric oxide synthase inhibition prevents acute quinolinate-induced striatal neurotoxicity,” Neurochemical Research, vol. 23, no. 10, pp. 1297–1302, 1998.
[51]
J. Cabrera, R. J. Reiter, D.-X. Tan et al., “Melatonin reduces oxidative neurotoxicity due to quinolinic acid: in vitro and in vivo findings,” Neuropharmacology, vol. 39, no. 3, pp. 507–514, 2000.
[52]
M. Ganzella, F. M. Jardim, C. R. Boeck, and D. Vendite, “Time course of oxidative events in the hippocampus following intracerebroventricular infusion of quinolinic acid in mice,” Neuroscience Research, vol. 55, no. 4, pp. 397–402, 2006.
[53]
C. A. Ribeiro, V. Grando, C. S. Dutra Filho, C. M. Wannmacher, and M. Wajner, “Evidence that quinolinic acid severely impairs energy metabolism through activation of NMDA receptors in striatum from developing rats,” Journal of Neurochemistry, vol. 99, no. 6, pp. 1531–1542, 2006.
[54]
P. F. Schuck, A. Tonin, G. da Costa Ferreira et al., “In vitro effect of quinolinic acid on energy metabolism in brain of young rats,” Neuroscience Research, vol. 57, no. 2, pp. 277–288, 2007.
[55]
T. Blanco-Ayala, I. Serratos-Alvarez, M. Orozco-Ibarra, et al., “Effect of some kynurenines under succinate deshidrogenase activity and ATP production: in vitro experimental and computational tools,” in Neuroscience Meeting, vol. 60.09, Society for Neuroscience, New Orleans, LA, USA, 2012.
[56]
I. P. Lapin, S. M. Mirzaev, I. V. Ryzov, and G. F. Oxenkrug, “Anticonvulsant activity of melatonin against seizures induced by quinolinate, kainate, glutamate, NMDA, and pentylenetetrazole in mice,” Journal of Pineal Research, vol. 24, no. 4, pp. 215–218, 1998.
[57]
G. S. Southgate, S. Daya, and B. Potgieter, “Melatonin plays a protective role in quinolinic acid-induced neurotoxicity in the rat hippocampus,” Journal of Chemical Neuroanatomy, vol. 14, no. 3-4, pp. 151–156, 1998.
[58]
E. Antunes Wilhelm, C. Ricardo Jesse, C. Folharini Bortolatto, and C. Wayne Nogueira, “Correlations between behavioural and oxidative parameters in a rat quinolinic acid model of Huntington's disease: protective effect of melatonin,” European Journal of Pharmacology, vol. 701, no. 1–3, pp. 65–72, 2013.
[59]
W. M. H. Behan, M. McDonald, L. G. Darlington, and T. W. Stone, “Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl,” British Journal of Pharmacology, vol. 128, no. 8, pp. 1754–1760, 1999.
[60]
N. Nakao and P. Brundin, “Effects of α-phenyl-tert-butyl nitrone on neuronal survival and motor function following intrastriatal injections of quinolinate or 3-nitropropionic acid,” Neuroscience, vol. 76, no. 3, pp. 749–761, 1996.
[61]
N. A. V. Bellé, G. D. Dalmolin, G. Fonini, M. A. Rubin, and J. B. T. Rocha, “Polyamines reduces lipid peroxidation induced by different pro-oxidant agents,” Brain Research, vol. 1008, no. 2, pp. 245–251, 2004.
[62]
S. Stipek, F. Stastny, J. Platenik, J. Crkovska, and T. Zima, “The effect of quinolinate on rat brain lipid peroxidation is dependent on iron,” Neurochemistry International, vol. 30, no. 2, pp. 233–237, 1997.
[63]
A. Santamaría, S. Galván-Arzate, V. Lisy et al., “Quinolinic acid induces oxidative stress in rat brain synaptosomes,” NeuroReport, vol. 12, no. 4, pp. 871–874, 2001.
[64]
A. Santamaría, B. Vázquez-Román, V. Pérez-De La Cruz et al., “Selenium reduces the proapoptotic signaling associated to NF-κB pathway and stimulates glutathione peroxidase activity during excitotoxic damage produced by quinolinate in rat corpus striatum,” Synapse, vol. 58, no. 4, pp. 258–266, 2005.
[65]
A. Santamaría, R. Salvatierra-Sánchez, B. Vázquez-Román et al., “Protective effects of the antioxidant selenium on quinolinic acid-induced neurotoxicity in rats: in vitro and in vivo studies,” Journal of Neurochemistry, vol. 86, no. 2, pp. 479–488, 2003.
[66]
P. D. Maldonado, V. Perez-De La Cruz, M. Torres-Ramos, et al., “Selenium-induced antioxidant protection recruits modulation of thioredoxin reductase during excitotoxic/pro-oxidant events in the rat striatum,” Neurochemistry International, vol. 61, no. 2, pp. 195–206, 2012.
[67]
J. I. Rossato, G. Zeni, C. F. Mello, M. A. Rubin, and J. B. T. Rocha, “Ebselen blocks the quinolinic acid-induced production of thiobarbituric acid reactive species but does not prevent the behavioral alterations produced by intra-striatal quinolinic acid administration in the rat,” Neuroscience Letters, vol. 318, no. 3, pp. 137–140, 2002.
[68]
S. S. Swathy and M. Indira, “The Ayurvedic drug, Ksheerabala, ameliorates quinolinic acid-induced oxidative stress in rat brain,” International Journal of Ayurveda Research, vol. 1, no. 1, pp. 4–9, 2010.
[69]
H. Kalonia, P. Kumar, A. Kumar, and B. Nehru, “Protective effect of montelukast against quinolinic acid/malonic acid induced neurotoxicity: possible behavioral, biochemical, mitochondrial and tumor necrosis factor-α level alterations in rats,” Neuroscience, vol. 171, no. 1, pp. 284–299, 2010.
[70]
H. Kalonia, P. Kumar, and A. Kumar, “Pioglitazone ameliorates behavioral, biochemical and cellular alterations in quinolinic acid induced neurotoxicity: possible role of peroxisome proliferator activated receptor-υ (PPARυ) in Huntington's disease,” Pharmacology Biochemistry and Behavior, vol. 96, no. 2, pp. 115–124, 2010.
[71]
H. Kalonia, P. Kumar, and A. Kumar, “Licofelone attenuates quinolinic acid induced Huntington like symptoms: possible behavioral, biochemical and cellular alterations,” Progress in Neuro-Psychopharmacology & Biological Psychiatry, vol. 35, no. 2, pp. 607–615, 2011.
[72]
M. Misztal, T. Frankiewicz, C. G. Parsons, and W. Danysz, “Learning deficits induced by chronic intraventricular infusion of quinolinic acid—protection by MK-801 and memantine,” European Journal of Pharmacology, vol. 296, no. 1, pp. 1–8, 1996.
[73]
H. Kalonia, P. Kumar, B. Nehru, and A. Kumar, “Neuroprotective effect of MK-801 against intra-striatal quinolinic acid induced behavioral, oxidative stress and cellular alterations in rats,” Indian Journal of Experimental Biology, vol. 47, no. 11, pp. 880–892, 2009.
[74]
Y. Chen, B. J. Brew, and G. J. Guillemin, “Characterization of the kynurenine pathway in NSC-34 cell line: implications for amyotrophic lateral sclerosis,” Journal of Neurochemistry, vol. 118, no. 5, pp. 816–825, 2011.
[75]
H. Kalonia, P. Kumar, A. Kumar, and B. Nehru, “Effects of caffeic acid, rofecoxib, and their combination against quinolinic acid-induced behavioral alterations and disruption in glutathione redox status,” Neuroscience Bulletin, vol. 25, no. 6, pp. 343–352, 2009.
[76]
H. Kalonia, P. Kumar, A. Kumar, and B. Nehru, “Protective effect of rofecoxib and nimesulide against intra-striatal quinolinic acid-induced behavioral, oxidative stress and mitochondrial dysfunctions in rats,” NeuroToxicology, vol. 31, no. 2, pp. 195–203, 2010.
[77]
N. Braidy, R. Grant, S. Adams, B. J. Brew, and G. J. Guillemin, “Mechanism for quinolinic acid cytotoxicity in human astrocytes and neurons,” Neurotoxicity Research, vol. 16, no. 1, pp. 77–86, 2009.
[78]
J. H. Connick and T. W. Stone, “Quinolinic acid effects on amino acid release from the rat cerebral cortex in vitro and in vivo,” British Journal of Pharmacology, vol. 93, no. 4, pp. 868–876, 1988.
[79]
V. Pérez-De La Cruz, M. Konigsberg, J. Pedraza-Chaverri et al., “Cytoplasmic calcium mediates oxidative damage in an excitotoxic/energetic deficit synergic model in rats,” The European Journal of Neuroscience, vol. 27, no. 5, pp. 1075–1085, 2008.
[80]
D. Silva-Adaya, V. Pérez-De La Cruz, M. N. Herrera-Mundo et al., “Excitotoxic damage, disrupted energy metabolism, and oxidative stress in the rat brain: antioxidant and neuroprotective effects of L-carnitine,” Journal of Neurochemistry, vol. 105, no. 3, pp. 677–689, 2008.
[81]
D. Elinos-Calderón, Y. Robledo-Arratia, V. Pérez-De La Cruz, J. Pedraza-Chaverrí, S. F. Ali, and A. Santamaría, “Early nerve ending rescue from oxidative damage and energy failure by l-carnitine as post-treatment in two neurotoxic models in rat: recovery of antioxidant and reductive capacities,” Experimental Brain Research, vol. 197, no. 3, pp. 287–296, 2009.
[82]
A. Dairam, P. Chetty, and S. Daya, “Non-steroidal anti-inflammatory agents, tolmetin and sulindac, attenuate oxidative stress in rat brain homogenate and reduce quinolinic acid-induced neurodegeneration in rat hippocampal neurons,” Metabolic Brain Disease, vol. 21, no. 2-3, pp. 221–233, 2006.
[83]
A. Dairam, A. C. Müller, and S. Daya, “Non-steroidal anti-inflammatory agents, tolmetin and sulindac attenuate quinolinic acid (QA)-induced oxidative stress in primary hippocampal neurons and reduce QA-induced spatial reference memory deficits in male Wistar rats,” Life Sciences, vol. 80, no. 15, pp. 1431–1438, 2007.
[84]
A. C. Müller, H. Maharaj, D. S. Maharaj, and S. Daya, “Aciclovir protects against quinolinic-acid-induced oxidative neurotoxicity,” Journal of Pharmacy and Pharmacology, vol. 57, no. 7, pp. 883–888, 2005.
[85]
A. Santamaría, D. Santamaría, M. Díaz-Mu？oz, V. Espinoza-González, and C. Ríos, “Effects of Nω-nitro-L-arginine and L-arginine on quinolinic acid-induced lipid peroxidation,” Toxicology Letters, vol. 93, no. 2-3, pp. 117–124, 1997.
[86]
V. Pérez-De La Cruz, C. González-Cortés, S. Galván-Arzate et al., “Excitotoxic brain damage involves early peroxynitrite formation in a model of Huntington's disease in rats: protective role of iron porphyrinate 5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinate iron (III),” Neuroscience, vol. 135, no. 2, pp. 463–474, 2005.
[87]
D. Santiago-López, B. Vázquez-Román, V. Pérez-de la Cruz et al., “Peroxynitrite decomposition catalyst, iron metalloporphyrin, reduces quinolinate-induced neurotoxicity in rats,” Synapse, vol. 54, no. 4, pp. 233–238, 2004.
[88]
C. González-Cortés, C. Salinas-Lara, M. A. Gómez-López et al., “Iron porphyrinate Fe(TPPS) reduces brain cell damage in rats intrastriatally lesioned by quinolinate,” Neurotoxicology and Teratology, vol. 30, no. 6, pp. 510–519, 2008.
[89]
H. R. Sadeghnia, M. Kamkar, E. Assadpour, M. T. Boroushaki, and A. Ghorbani, “Protective effect of Safranal, a constituent of crocus sativus, on quinolinic acid-induced oxidative damage in rat hippocampus,” Iranian Journal of Basic Medical Sciences, vol. 16, no. 1, pp. 73–82, 2013.
[90]
N. Braidy, R. Grant, S. Adams, and G. J. Guillemin, “Neuroprotective effects of naturally occurring polyphenols on quinolinic acid-induced excitotoxicity in human neurons,” The FEBS Journal, vol. 277, no. 2, pp. 368–382, 2010.
[91]
E. Gulaj, K. Pawlak, B. Bien, and D. Pawlak, “Kynurenine and its metabolites in Alzheimer's disease patients,” Advances in Medical Sciences, vol. 55, no. 2, pp. 204–211, 2010.
[92]
W. Wu, J. A. Nicolazzo, L. Wen et al., “Expression of tryptophan 2, 3-dioxygenase and production of kynurenine pathway metabolites in triple transgenic mice and human Alzheimer's disease brain,” PloS One, vol. 8, no. 4, Article ID e59749, 2013.
[93]
G. J. Guillemin, G. A. Smythe, L. A. Veas, O. Takikawa, and B. J. Brew, “A beta 1-42 induces production of quinolinic acid by human macrophages and microglia,” Neuroreport, vol. 14, no. 18, pp. 2311–2315, 2003.
[94]
P. Guidetti, R. E. Luthi-Carter, S. J. Augood, and R. Schwarcz, “Neostriatal and cortical quinolinate levels are increased in early grade Huntington's disease,” Neurobiology of Disease, vol. 17, no. 3, pp. 455–461, 2004.
[95]
P. Guidetti, G. P. Bates, R. K. Graham et al., “Elevated brain 3-hydroxykynurenine and quinolinate levels in Huntington disease mice,” Neurobiology of Disease, vol. 23, no. 1, pp. 190–197, 2006.
[96]
M. P. Heyes, K. Saito, A. Lackner, C. A. Wiley, C. L. Achim, and S. P. Markey, “Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques,” FASEB Journal, vol. 12, no. 10, pp. 881–896, 1998.
[97]
M. P. Heyes, B. J. Brew, K. Saito et al., “Inter-relationships between quinolinic acid, neuroactive kynurenines, neopterin and β2-microglobulin in cerebrospinal fluid and serum of HIV-1-infected patients,” Journal of Neuroimmunology, vol. 40, no. 1, pp. 71–80, 1992.
[98]
G. J. Guillemin, S. J. Kerr, and B. J. Brew, “Involvement of quinolinic acid in aids dementia complex,” Neurotoxicity Research, vol. 7, no. 1-2, pp. 103–123, 2005.
[99]
S. Erhardt, C. K. Lim, K. R. Linderholm, et al., “Connecting inflammation with glutamate agonism in suicidality,” Neuropsychopharmacology, vol. 38, no. 5, pp. 743–752, 2013.
[100]
J. Steiner, M. Walter, T. Gos et al., “Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission?” Journal of Neuroinflammation, vol. 8, article 94, 2011.
[101]
A. W. Zimmerman, H. Jyonouchi, A. M. Comi et al., “Cerebrospinal fluid and serum markers of inflammation in autism,” Pediatric Neurology, vol. 33, no. 3, pp. 195–201, 2005.
[102]
Y. Chen, R. Stankovic, K. M. Cullen et al., “The kynurenine pathway and inflammation in amyotrophic lateral sclerosis,” Neurotoxicity Research, vol. 18, no. 2, pp. 132–142, 2010.
[103]
E. M. Flanagan, J. B. Erickson, O. H. Viveros, S. Y. Chang, and J. F. Reinhard Jr., “Neurotoxin quinolinic acid is selectively elevated in spinal cords of rats with experimental allergic encephalomyelitis,” Journal of Neurochemistry, vol. 64, no. 3, pp. 1192–1196, 1995.
[104]
J. Füvesi, C. Rajda, K. Bencsik, J. Toldi, and L. Vécsei, “The role of kynurenines in the pathomechanism of amyotrophic lateral sclerosis and multiple sclerosis: therapeutic implications,” Journal of Neural Transmission, vol. 119, no. 2, pp. 225–234, 2012.
[105]
H. Iwahashi, H. Kawamori, and K. Fukushima, “Quinolinic acid, α-picolinic acid, fusaric acid, and 2,6-pyridinedicarboxylic acid enhance the Fenton reaction in phosphate buffer,” Chemico-Biological Interactions, vol. 118, no. 3, pp. 201–215, 1999.
[106]
K. Goda, R. Kishimoto, S. Shimizu, Y. Hamane, and M. Ueda, “Quinolinic acid and active oxygens. Possible contribution of active Oxygens during cell death in the brain,” Advances in Experimental Medicine and Biology, vol. 398, pp. 247–254, 1996.
[107]
V. Perez-De La Cruz, D. Elinos-Calderón, P. Carrillo-Mora et al., “Time-course correlation of early toxic events in three models of striatal damage: modulation by proteases inhibition,” Neurochemistry International, vol. 56, no. 6-7, pp. 834–842, 2010.
[108]
E. Rodríguez-Martínez, A. Camacho, P. D. Maldonado et al., “Effect of quinolinic acid on endogenous antioxidants in rat corpus striatum,” Brain Research, vol. 858, no. 2, pp. 436–439, 2000.
[109]
A. Santamaría, M. E. Jiménez-Capdeville, A. Camacho, E. Rodríguez-Martínez, A. Flores, and S. Galván-Arzate, “In vivo hydroxyl radical formation after quinolinic acid infusion into rat corpus striatum,” NeuroReport, vol. 12, no. 12, pp. 2693–2696, 2001.
[110]
G. Leipnitz, C. Schumacher, K. Scussiato et al., “Quinolinic acid reduces the antioxidant defenses in cerebral cortex of young rats,” International Journal of Developmental Neuroscience, vol. 23, no. 8, pp. 695–701, 2005.
[111]
H. Noack, J. Lindenau, F. Rothe, K. Asayama, and G. Wolf, “Differential expression of superoxide dismutase isoforms in neuronal and glial compartments in the course of excitotoxically mediated neurodegeneration: relation to oxidative and nitrergic stress,” Glia, vol. 23, no. 4, pp. 285–297, 1998.
[112]
C. Tronel, G. Y. Rochefort, N. Arlicot, S. Bodard, S. Chalon, and D. Antier, “Oxidative stress is related to the deleterious effects of heme oxygenase-1 in an in vivo neuroinflammatory rat model,” Oxidative Medicine and Cellular Longevity, vol. 2013, Article ID 264935, 10 pages, 2013.
[113]
M. P. Heyes, C. Y. Chen, E. O. Major, and K. Saito, “Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types,” The Biochemical Journal, vol. 326, no. 2, pp. 351–356, 1997.
[114]
M. G. Espey, J. R. Moffett, and M. A. A. Namboodiri, “Temporal and spatial changes of quinolinic acid immunoreactivity in the immune system of lipopolysaccharide stimulated mice,” Journal of Leukocyte Biology, vol. 57, no. 2, pp. 199–206, 1995.
[115]
R. Hanbury, Z. D. Ling, J. Wuu, and J. H. Kordower, “GFAP knockout mice have increased levels of GDNF that protect striatal neurons from metabolic and excitotoxic insults,” Journal of Comparative Neurology, vol. 461, no. 3, pp. 307–316, 2003.
[116]
G. J. Guillemin, J. Croitoru-Lamoury, D. Dormont, P. J. Armati, and B. J. Brew, “Quinolinic acid upregulates chemokine production and chemokine receptor expression in astrocytes,” GLIA, vol. 41, no. 4, pp. 371–381, 2003.
[117]
K. E. Beagles, P. F. Morrison, and M. P. Heyes, “Quinolinic acid in vivo synthesis rates, extracellular concentrations, and intercompartmental distributions in normal and immune-activated brain as determined by multiple-isotope microdialysis,” Journal of Neurochemistry, vol. 70, no. 1, pp. 281–291, 1998.
[118]
F. Block and M. Schwarz, “Expression of GFAP in the striatum and its projection areas in response to striatal quinolinic acid lesion in rats,” NeuroReport, vol. 5, no. 17, pp. 2237–2240, 1994.
[119]
J. Schiefer, R. T？pper, W. Schmidt et al., “Expression of interleukin 6 in the rat striatum following stereotaxic injection of quinolinic acid,” Journal of Neuroimmunology, vol. 89, no. 1-2, pp. 168–176, 1998.
[120]
H. Kalonia and A. Kumar, “Suppressing inflammatory cascade by cyclo-oxygenase inhibitors attenuates quinolinic acid induced Huntington's disease-like alterations in rats,” Life Sciences, vol. 88, no. 17-18, pp. 784–791, 2011.
[121]
S. G. Wilt, E. Milward, J. M. Zhou et al., “In vitro evidence for a dual role of tumor necrosis factor-α in human immunodeficiency virus type 1 encephalopathy,” Annals of Neurology, vol. 37, no. 3, pp. 381–394, 1995.
[122]
W. Cammer, “Oligodendrocyte killing by quinolinic acid in vitro,” Brain Research, vol. 896, no. 1-2, pp. 157–160, 2001.
[123]
J. S. Pober and R. S. Cotran, “Cytokines and endothelial cell biology,” Physiological Reviews, vol. 70, no. 2, pp. 427–451, 1990.
[124]
K. Schulze-Osthoff, A. C. Bakker, B. Vanhaesebroeck, R. Beyaert, W. A. Jacob, and W. Fiers, “Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation,” The Journal of Biological Chemistry, vol. 267, no. 8, pp. 5317–5323, 1992.
[125]
M. Hayashi, Y. Luo, J. Laning, R. M. Strieter, and M. E. Dorf, “Production and function of monocyte chemoattractant protein-1 and other β-chemokines in murine glial cells,” Journal of Neuroimmunology, vol. 60, no. 1-2, pp. 143–150, 1995.
[126]
M. P. Heyes, “Quinolinic acid and inflammation,” Annals of the New York Academy of Sciences, vol. 679, pp. 211–216, 1993.
[127]
P. R. Sanberg, S. F. Calderon, M. Giordano, J. M. Tew, and A. B. Norman, “The quinolinic acid model of Huntington's disease: locomotor abnormalities,” Experimental Neurology, vol. 105, no. 1, pp. 45–53, 1989.
[128]
V. Pérez-De La Cruz, D. Elinos-Calderón, Y. Robledo-Arratia et al., “Targeting oxidative/nitrergic stress ameliorates motor impairment, and attenuates synaptic mitochondrial dysfunction and lipid peroxidation in two models of Huntington's disease,” Behavioural Brain Research, vol. 199, no. 2, pp. 210–217, 2009.
[129]
D. A. Shear, J. Dong, K. L. Haik-Creguer, T. J. Bazzett, R. L. Albin, and G. L. Dunbar, “Chronic administration of quinolinic acid in the rat striatum causes spatial learning deficits in a radial arm water maze task,” Experimental Neurology, vol. 150, no. 2, pp. 305–311, 1998.
[130]
E. M. Vazey, K. Chen, S. M. Hughes, and B. Connor, “Transplanted adult neural progenitor cells survive, differentiate and reduce motor function impairment in a rodent model of Huntington's disease,” Experimental Neurology, vol. 199, no. 2, pp. 384–396, 2006.
[131]
E. G. McGeer and E. Singh, “Neurotoxic effects of endogenous materials: quinolinic acid, L-pyroglutamic acid, and thyroid releasing hormone (TRH),” Experimental Neurology, vol. 86, no. 2, pp. 410–413, 1984.
[132]
A. P. Kells, R. A. Henry, and B. Connor, “AAV-BDNF mediated attenuation of quinolinic acid-induced neuropathology and motor function impairment,” Gene Therapy, vol. 15, no. 13, pp. 966–977, 2008.
[133]
C. Portera-Cailliau, D. L. Price, and L. J. Martin, “Non-NMDA and NMDA receptor-mediated excitotoxic neuronal deaths in adult brain are morphologically distinct: further evidence for an apoptosis-necrosis continuum,” The Journal of Comparative Neurology, vol. 378, no. 1, pp. 88–104, 1997.
[134]
K. Ishidoh, N. Kamemura, T. Imagawa, M. Oda, J. Sakurai, and N. Katunuma, “Quinolinate phosphoribosyl transferase, a key enzyme in de novo NAD+ synthesis, suppresses spontaneous cell death by inhibiting overproduction of active-caspase-3,” Biochimica et Biophysica Acta, vol. 1803, no. 5, pp. 527–533, 2010.
[135]
A. Macaya, F. Munell, R. M. Gubits, and R. E. Burke, “Apoptosis in substantia nigra following developmental striatal excitotoxic injury,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 17, pp. 8117–8121, 1994.
[136]
B. S. Jeon, N. G. Kholodilov, T. F. Oo et al., “Activation of caspase-3 in developmental models of programmed cell death in neurons of the substantia nigra,” Journal of Neurochemistry, vol. 73, no. 1, pp. 322–333, 1999.
[137]
G. J. Guillemin, L. Wang, and B. J. Brew, “Quinolinic acid selectively induces apoptosis of human astocytes: potential role in AIDS dementia complex,” Journal of Neuroinflammation, vol. 2, article 16, 2005.
[138]
P. E. Hughes, T. Alexi, T. Yoshida, S. S. Schreiber, and B. Knusel, “Excitotoxic lesion of rat brain with quinolinic acid induces expression of p53 messenger RNA and protein and p53-inducible genes Bax and Gadd-45 in brain areas showing DNA fragmentation,” Neuroscience, vol. 74, no. 4, pp. 1143–1160, 1996.
[139]
Y. M. Bordelon, L. Mackenzie, and M. F. Chesselet, “Morphology and compartmental location of cells exhibiting DNA damage after quinolinic acid injections into rat striatum,” The Journal of Comparative Neurology, vol. 412, no. 1, pp. 38–50, 1999.
[140]
H. Wei, Z.-H. Qin, V. V. Senatorov et al., “Lithium suppresses excitotoxicity-induced striatal lesions in a rat model of Huntington's disease,” Neuroscience, vol. 106, no. 3, pp. 603–612, 2001.
[141]
E. Pérez-Navarro, N. Gavaldà, E. Gratacòs, and J. Alberch, “Brain-derived neurotrophic factor prevents changes in Bcl-2 family members and caspase-3 activation induced by excitotoxicity in the striatum,” Journal of Neurochemistry, vol. 92, no. 3, pp. 678–691, 2005.
[142]
Z.-H. Qin, Y. Wang, and T. N. Chasea, “A caspase-3-like protease is involved in NF-κB activation induced by stimulation of N-methyl-d-aspartate receptors in rat striatum,” Molecular Brain Research, vol. 80, no. 2, pp. 111–122, 2000.
[143]
Y. Wang, X.-X. Dong, Y. Cao et al., “P53 induction contributes to excitotoxic neuronal death in rat striatum through apoptotic and autophagic mechanisms,” The European The Journal of Neuroscience, vol. 30, no. 12, pp. 2258–2270, 2009.
