Quinolinic acid accumulation during neuroinflammation. Does it imply excitotoxicity?
It is often proposed that quinolinic acid (QUIN) contributes to the pathophysiology of neuroinflammation because this kynurenine pathway metabolite is a selective agonist of N-methyl-D-aspartate (NMDA) receptors, and both its brain tissue and cerebrospinal fluid concentrations increase markedly with inflammation. However, whether or not the extracellular levels of QUIN reached during neuroinflammation are high enough to promote excitotoxicity, remains unclear because QUIN is a weak NMDA receptor agonist. We have addressed this issue by evaluating the extracellular concentrations of QUIN that must be reached to initiate potentially excitotoxic changes in the cerebral cortex of rats, under normal conditions, and when superimposed on another insult. We have also examined the increase in extracellular lactate associated with the perfusion of increasing concentrations of QUIN through a microdialysis probe. The extracellular EC50 for induction of local depolarisation was 228 microM with QUIN alone; that is, about 30 times the levels of QUIN measured previously in immune activated brain. Furthermore, at least 20 microM extracellular QUIN needed to be reached to reduce K+ induced spreading depression, an unexpected effect since spreading depression is inhibited by NMDA receptor antagonists. Our data suggest that, although synthesis of QUIN from activated microglia and invading macrophages can increase its extracellular concentration 10-100-fold, the levels that are reached in these conditions remain far below the concentrations of QUIN that are necessary for excessive NMDA receptor activation. However, the possibility that QUIN accumulation may be a deleterious feature of neuroinflammation cannot be ruled out at this stage.
Obrenovitch
T P
TP
School of Pharmacy, University of Bradford, Bradford BD7 1DP, U.K. t.obrenovitch@bradford.ac.uk
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D013181:Cortical Spreading Depression / Q000187:drug effects* / Q000502:physiology; D004660:Encephalitis / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D011188:Potassium / Q000494:pharmacology; D017378:Quinolinic Acid / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism
D016194:Receptors, N-Methyl-D-Aspartate; D019344:Lactic Acid; D017378:Quinolinic Acid; D011188:Potassium