In vivo assessment of kynurenate neuroprotective potency and quinolinate excitotoxicity.
Three complementary questions related to the kynurenine pathway and excitotoxicity were addressed in this study: (i) Which extracellular levels of quinolinic acid (QUIN) may be neurotoxic? (ii) Which extracellular levels of kynurenic acid (KYNA) may control excessive NMDA-receptor function? (iii) Can "anti-excitotoxic" levels of KYNA be reached by inhibition of kynurenine-3-hydroxylase (i.e. inhibition of QUIN synthesis and shunts of kynurenine metabolism toward KYNA)? Multifunctional microdialysis probes were used in halothane anaesthetised rats to apply NMDA or QUIN directly to the brain, with or without co-perfusion of KYNA, to record the resulting local depolarisations, and to monitor changes in dialysate KYNA after kynurenine-3-hydroxylase inhibition. QUIN produced concentration-dependent depolarisations with an estimated EC50 (i.e. concentration in the perfusion medium) of 1.22mM. The estimated ED50 for KYNA inhibition of NMDA-responses was 181microM. Kynurenine-3-hydroxylase inhibition (Ro-61-8048, 100mg/kg i.p.) increased dialysate KYNA 11 times (to 33.8nM) but without any reduction of NMDA-responses. These data challenge the notion that extracellular accumulation of endogenous QUIN may contribute to excessive NMDA-receptor activation in some neurological disorders, and the suitability of kynurenine-3-hydroxylase inhibition as an effective anti-excitotoxic strategy.
Obrenovitch
T P
TP
Pharmacology, School of Pharmacy, University of Bradford, United Kingdom. t.obrenovitch@bradford.ac.uk
Urenjak
J
J
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D007736:Kynurenic Acid / Q000494:pharmacology*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000378:metabolism*; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; C110196:Ro 61-8048; D013449:Sulfonamides; D013844:Thiazoles; D017378:Quinolinic Acid; D007736:Kynurenic Acid