Abstract
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;1’3’4(ii) QUIN is an agonist of N-methylD-aspartate (NMDA) receptors.5’6However, 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.5’6
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).
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Obrenovitch, T.P., Urenjak, J. (2003). Accumulation of Quinolinic Acid With Neuroinflammation: Does It Mean Excitotoxicity?. In: Allegri, G., Costa, C.V.L., Ragazzi, E., Steinhart, H., Varesio, L. (eds) Developments in Tryptophan and Serotonin Metabolism. Advances in Experimental Medicine and Biology, vol 527. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0135-0_17
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