Accumulation of Quinolinic Acid With Neuroinflammation: Does It Mean Excitotoxicity?

  • Tiho P. Obrenovitch
  • Jutta Urenjak
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 527)


The quinolinic acid (QUIN) accumulation that is associated with neuroinflammation is often considered capable of promoting excitotoxic neuronal damage, but QUIN is a relatively weak agonist of N-methyl-D-aspartate (NMDA) receptors. Our study aimed to determinein vivowhich extracellular concentrations of QUIN must be reached to initiate electrophysiological changes indicative of excitotoxic stress in the cerebral cortex of rats, under normal conditions and when superimposed to a challenge involving NMDA-receptor activation, i.e. repeated cortical spreading depression (CSD). Our experimental strategy relied on microdialysis probes incorporating an electrode, implanted in the brain of halothane-anaesthetised rats. These devices were used to apply QUIN or NMDA locally to the cortical area under study (with or without co-perfusion of high K’ for repetitive induction of CSD), and to record the associated changes in the extracellular DC potential (for information on the membrane polarisation of the cellular population surrounding the probe) and lactate (for the detection of increased local energy demand).

The extracellular EC50for induction of local depolarisation in the normal cortex was around 30 times higher than the extracellular QUIN levels measured in the immunoactivated brain of gerbils. Within the range of concentrations 0.03 to 0.3 mM in the perfusion medium, QUIN suppressed concentration-dependently the elicitation of CSD by K’, presumably because of NMDA-receptor desensitisation. Finally, on-line monitoring of changes in extracellular lactate with local application of QUIN indicated that extracellular concentration of QUIN in the low micromolar range are well tolerated by the brain parenchyma, at least in cortical regions. All these data do not support the notion that QUIN accumulation adds an excitotoxic component to neuroinflammation.

the kynurenine pathway in invading macrophages and activated microglia;134(ii) QUIN is an agonist of N-methylD-aspartate (NMDA) receptors.56However, QUIN is a relatively weak agonist of NMDA-receptors,’ and millimolar concentrations of this excitotoxin had to be microinjected in the striatum of rats to cause acute neurodegeneration.56

Ourin vivostudies had two complementary objectives: (i) To determine which extracellular concentrations of QUIN must be reached to initiate electrophysiological changes indicative of excitotoxic stress in the cerebral cortex of rats under normal conditions; and (ii) to examine how increased extracellular concentrations of QUIN alter a well-characterised phenomenon that involves glutamate/NMDA-receptor-mediated synaptic transmission, i.e. cortical spreading depression (CSD).


Quinolinic Acid Cortical Spreading Depression Microdialysis Probe Kynurenine Pathway Intracerebral Microdialysis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    M.P. Heyes, The kynurenine pathway and neurologic disease. Therapeutic strategiesAdv. Exp. Med. Biol.398,125–129 (1996).PubMedCrossRefGoogle Scholar
  2. 2.
    G.J. Guillemin, S.J. Kerr, G.A. Smythe, D.G. Smith, V. Kapoor, P.J. Armati, J. Croitoru, B.J. Brew, Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protectionJ. Neurochem.78, 842–853 (2001).PubMedCrossRefGoogle Scholar
  3. 3.
    D. Alberati-Giani, P. Ricciardi-Castagnoli, C. Köhler, A.M. Cesura, Regulation of the kynurenine metabolic pathway by interferon-y in murine cloned macrophages and microglial cellsJ. Neurochem. 66996–1004 (1996).PubMedCrossRefGoogle Scholar
  4. 4.
    G.J. Guillemin, S.J. Kerr, L.A. Pemberton, D.G. Smith, G.A. Smythe, P.J. Armati, J. Croitoru, B.J. Brew, lFN-01b induces kynurenine pathway metabolism in human macrophages: potential implications for multiple sclerosis treatmentJ. Interferon Cytokine Res. 211097–1101 (2001).PubMedCrossRefGoogle Scholar
  5. 5.
    R. Schwarcz, W.O. Jr. Whetsell, R.M. Mangano, Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brainScience 219316–318 (1983).PubMedCrossRefGoogle Scholar
  6. 6.
    M. Levivier, S. Przedborski, Quinolinic acid-induced lesions of the rat striatum: quantitative autoradiographic binding assessmentNeurol. Res. 2046–56 (1998).PubMedGoogle Scholar
  7. 7.
    M.C. Curras, R. Dingledine, Selectivity of amino acid transmitters acting at N-methyl-D-aspartate and amino-3hydroxy-5-methyl-isoxazoleproprionate receptorsMo!. Pharmacol. 41520–526 (1992).Google Scholar
  8. 8.
    T.P. Obrenovitch, D.A. Richards, G.S. Sama, L. Symon, Combined intracerebral microdialysis and electrophysiological recording: Methodology and applicationsJ. Neurosci. Meth. 47139–145 (1993).CrossRefGoogle Scholar
  9. 9.
    T.P. Obrenovitch J. Urenjak, E. Zilkha Intracerebral microdialysis combined with recording of extracellular field potential: a novel method for investigation of depolarizing drugsin vivo Br. J. Pharmacol. 113 1295–1302 (1994).PubMedCrossRefGoogle Scholar
  10. 10.
    T.P. Obrenovitch, J. Urenjak, E. Zilkha. Intracerebral microdialysis combinedwithrecording of extracellular field potential: a novel method for investigation of depolarizing drugsin vivo Br. J. Pharmacol. 1131295–1302 (1994).PubMedCrossRefGoogle Scholar
  11. 11.
    R. Exley, E. Zilkha, J. Urenjak, T.P. Obrenovitch, Continuous monitoring of changes in brain extracellular lactate using microdialysis coupled to enzyme-amperometric analysisBr. J. Pharmacol. 131(Suppl.)219 (2000).Google Scholar
  12. 12.
    K.E. Beagles, P.F. Morrison, M.P. Heyes, Quinolinicacid in vivosynthesis rates, extracellular concentrations, and intercompartmental distributions in normal and immune-activated brain as determined by multiple-isotope microdialysisJ. Neurochem. 70281–291 (1998).PubMedCrossRefGoogle Scholar
  13. 13.
    M. Minervini, A. Atlante, S. Gagliardi, M.T. Ciotti, E. Marra, P. Calissano, Glutamate stimulates 2deoxyglucose uptake in rat cerebellar granule cellsBrain Res. 76857–62 (1997).PubMedCrossRefGoogle Scholar
  14. 14.
    Y.M. Bordelon, M.-F. Chesselet, M. Erecinska, I.A. Silver, EtTects of intrastriatal injection of quinolinic acid on electrical activity and extracellular ion concentrations in rat striatumin vivo Neuroscience 83459–469 (1998).PubMedCrossRefGoogle Scholar
  15. 15.
    M. Demestre, M. Boutelle, M. Fillenz, Stimulated release of lactate in freely moving rats is dependent on the uptake of glutamateJ. Physiol. 499825–832 (1997)PubMedGoogle Scholar
  16. 16.
    A.E. Fray, R.J. Forsyth, M.G. Boutelle, M. Fillenz, The mechanisms controlling physiologically stimulated changes in rat brain glucose and lactate: a microdialysis studyJ. Physiol. 49649–57 (1996).PubMedGoogle Scholar
  17. 17.
    T.P. Obrenovitch TP, E. Zilkha, Microdialysis coupled to online enzymatic assaysMethods 2363–71 (2001).PubMedCrossRefGoogle Scholar
  18. 18.
    T.P. Obrenovitch, E. Zilkha, Inhibition of cortical spreading depression by L-701,324, a novel antagonist at the glycine site of the N-methyl-D-aspartate receptor complexBr. J. Pharmacol. 117931–937 (1996).PubMedCrossRefGoogle Scholar
  19. 19.
    F.S. Menniti, M.J. Pagnozzi, P. Butler, B.L. Chenard, S.S. Jaw-Tsai, W. Frost, White CP-101,606, an NR2B subunit selective NMDA receptor antagonist, inhibits NMDA and injury induced c-fos expression and cortical spreading depression in rodentsNeuropharmacology 391147–1155 (2000).PubMedCrossRefGoogle Scholar
  20. 20.
    T.P. Obrenovitch, E. Zilkha, J. Urenja, Evidence against high extracellular glutamate promoting the elicitation of spreading depression by potassiumJ. Cereb. Blood Flow Melab.16,923–93 I (1996).CrossRefGoogle Scholar
  21. 21.
    W.O. Whetsell, R. Schwarcz, Prolonged exposure to submicromolar concentrations of quinolinic acid causes excitotoxic damage in organotypic cultures of rat corticostriatal systemNeurosci. Lett 97271–275 (1989).PubMedCrossRefGoogle Scholar
  22. 22.
    S.J. Kerr, P.J. Armati, G.J. Guillemin, B.J. Brew, Chronic exposure of human neurons to quinolinic acid results in neuronal changes consistent with AIDS dementia complex.AIDS 12, 3555–363 (1998).CrossRefGoogle Scholar
  23. 23.
    R. Balazs, N. Hack, O.S. Jorgensen, C.W. Cotman, N-methyl-D-aspartate promotes the survival of cerebellar granule cells: pharmacological considerationsNeurosci. Lett. 101,242–246 (1989).CrossRefGoogle Scholar
  24. 24.
    D.M. Chuang, X.M. Gao, S.M. Paul, N-methyl-D-aspartate exposure blocks glutamate toxicity in cultured cerebellar granule cellsMol. Pharmacol. 42,210–216 (1992).PubMedGoogle Scholar
  25. 25.
    N.J. Pantazis, D.P. Dohrman, J. Luo, J.D. Thomas, C.R. Goodlett, J.R. West, NMDA prevents alcohol-induced neuronal cell death of cerebellar granule cells in cultureAlcohol Clin. Exp. Res 19, 846–853 (1995).PubMedCrossRefGoogle Scholar
  26. 26.
    A.M. Marini, Y. Ueda, C.H. June, Intracellular survival pathways against glutamate receptor agonist excitotoxicity in cultured neurons. Intracellular calcium responsesAnn. N.Y. Acad. Sci. 890,421–437 (1999).PubMedCrossRefGoogle Scholar
  27. 27.
    A.M. Marini, S.J. Rabin, R.H. Lipsky, I. Mocchetti, Activity-dependent release of brain-derived neurotrophic factor underlies the neuroprotective effect of N-methyl-D-aspartateJ. Biol. Chem. 273,29394–29399 (1998).PubMedCrossRefGoogle Scholar
  28. 28.
    Y. Sei, L. Fossom, G. Gaping, P. Skolnick, A.S. Basile, Quinolinic acid protects rat cerebellar granule cells from glutamate-induced apoptosisNeurosci. Lett. 241,180–184 (1998).PubMedCrossRefGoogle Scholar
  29. 29.
    Z.H. Qin, R.W. Chen, Y. Wang, M. Nakai, D.M. Chuang, T.N. Chase, Nuclear factor kappaB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatumJ. Neurosci. 19,4023–4033 (1999).PubMedGoogle Scholar
  30. 30.
    W.M. Behan, M. McDonald, L.G. Darlington, T.W. Stone, Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenylBr. J. Pharmacol. 128,1754–1760 (1999).CrossRefGoogle Scholar
  31. 31.
    T.W. Stone. Endogenous neurotoxins from tryptophanToxicon. 39,61–73 (2001).PubMedCrossRefGoogle Scholar
  32. 32.
    H. Lehnert, R.J. Wurtman, Amino acid control of neurotransmitter synthesis and release: physiological and clinical implicationsPsychother. Psychosom. 60,18–32 (1993).PubMedCrossRefGoogle Scholar
  33. 33.
    F.A. Moreno, C. McGavin, T.P. Malan, A.J. Gelenberg, G.R. Heninger, A.A. Mathe, P.L. Delgado, Tryptophan depletion selectively reduces CSF 5-HT metabolites in healthy young men: results from single lumbar puncture sampling techniqueInt. J. Neuropsychopharmacol. 3.277–283 (2000).PubMedCrossRefGoogle Scholar
  34. 34.
    C. Bell, J. Abrams, D. Nutt, Tryptophan depletion and its implications for psychiatryBr. J. Psychiatry 178,399–405 (2001).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Tiho P. Obrenovitch
    • 1
  • Jutta Urenjak
    • 1
  1. 1.Pharmacology, School of PharmacyUniversity of Bradford, BradfordUK

Personalised recommendations