| Autor: |
Urenjak, Jutta, Obrenovitch, Tihomir P. |
| Předmět: |
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| Zdroj: |
Journal of Neurochemistry; Dec2000, Vol. 75 Issue 6, p2427, 7p, 4 Diagrams, 1 Graph |
| Abstrakt: |
Abstract: Inhibition of kynurenine 3-hydroxylase sup-presses quinolinic acid synthesis and, therefore, shunts all kynurenine metabolism toward kynurenic acid (KYNA) formation. This may be a pertinent antiexcitotoxic strat-egy because quinolinic acid is an agonist of NMDA re-ceptors, whereas kynurenic acid antagonises all iono-tropic glutamate receptors with preferential affinity for the NMDA receptor glycine site. We have examined whether the kynurenine 3-hydroxylase inhibitor Ro 61-8048 in-creases extracellular (KYNA) sufficiently to control exces-sive NMDA receptor function. Microdialysis probes incor-porating 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 dia-lysate 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 depolari-sations was not reduced. A separate study suggested that extracellular KYNA would need to be increased fur-ther 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. Key Words: Excitotoxicity--Kynurenine 3-hydroxylase--Kynurenic acid--Microdialysis--Ro 61-8048--N-Methyl-D- aspartate receptor. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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