Kynurenine 3-hydroxylase inhibition in rats: effects on extracellular kynurenic acid concentration and N-methyl-D-aspartate-induced depolarisation in the striatum.
Inhibition of kynurenine 3-hydroxylase suppresses quinolinic acid synthesis and, therefore, shunts all kynurenine metabolism toward kynurenic acid (KYNA) formation. This may be a pertinent antiexcitotoxic strategy because quinolinic acid is an agonist of NMDA receptors, whereas kynurenic acid antagonises all ionotropic glutamate receptors with preferential affinity for the NMDA receptor glycine site. We have examined whether the kynurenine 3-hydroxylase inhibitor Ro 61-8048 increases extracellular (KYNA) sufficiently to control excessive NMDA receptor function. Microdialysis probes incorporating an electrode were implanted into the striatum of anaesthetised rats, repeated NMDA stimuli were applied through the probe, and the resulting depolarisation was recorded. Changes in extracellular KYNA were assessed by HPLC analysis of consecutive dialysate samples. Ro 61-8048 (42 or 100 mg/kg) markedly increased the dialysate levels of KYNA. The maximum increase (from 3.0 +/- 1.0 to 31.0 +/- 6.0 nM; means +/- SEM, n = 6) was observed 4 h after administration of 100 mg/kg Ro 61-8048, but the magnitude of the NMDA-induced depolarisations was not reduced. A separate study suggested that extracellular KYNA would need to be increased further by two orders of magnitude to become effective in this preparation. These results challenge the notion that kynurenine 3-hydroxylase inhibition may be neuroprotective, primarily through accumulation of KYNA and subsequent attenuation of NMDA receptor function.
Urenjak
J
J
Pharmacology, School of Pharmacy, University of Bradford, Bradford, England.
Obrenovitch
T P
TP
D000284:Administration, Oral; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004569:Electroencephalography / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005110:Extracellular Space / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007736:Kynurenic Acid / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D017551:Microdialysis; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016202:N-Methylaspartate / Q000378:metabolism* / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage; D013844:Thiazoles / Q000008:administration & dosage
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; C110196:Ro 61-8048; D013449:Sulfonamides; D013844:Thiazoles; D016202:N-Methylaspartate; D006899:Mixed Function Oxygenases; D050601:Kynurenine 3-Monooxygenase; D007736:Kynurenic Acid