Neuroprotective potency of kynurenic acid against excitotoxicity.
The aim of this study was to determine in vivo which extracellular levels of kynurenic acid (KYNA) are required to control excessive NMDA receptor activation in the rat cortex. As excitotoxicity is coupled to marked ion movements, local depolarisations induced by perfusion of NMDA or quinolinic acid (QUIN) through microdialysis probes were recorded at the site of excitotoxin application. Perfusion of KYNA through the dialysis fibre inhibited the excitotoxin responses with an IC50 of 32-66 microM (extracellular concentration corrected for microdialysis delivery), but > 10-fold lower levels of endogenous KYNA were reported to be neuroprotective. Accordingly, these results strengthen the notion that KYNA accumulation may protect the brain parenchyma by acting on different molecular target(s), besides the NMDA receptor glycine site.
Urenjak
J
J
Department of Pharmacology, School of Pharmacy, University of Bradford, UK.
Obrenovitch
T P
TP
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D007736:Kynurenic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D017378:Quinolinic Acid; D007736:Kynurenic Acid