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Kynurenine 3‐Hydroxylase Inhibition in Rats

Kynurenine 3‐Hydroxylase Inhibition in Rats Abstract: Inhibition of kynurenine 3‐hydroxylase suppressesquinolinic acid synthesis and, therefore, shunts all kynurenine metabolismtoward kynurenic acid (KYNA) formation. This may be a pertinentantiexcitotoxic strategy because quinolinic acid is an agonist of NMDAreceptors, whereas kynurenic acid antagonises all ionotropic glutamatereceptors with preferential affinity for the NMDA receptor glycine site. Wehave examined whether the kynurenine 3‐hydroxylase inhibitor Ro 61‐8048increases extracellular (KYNA) sufficiently to control excessive NMDA receptorfunction. Microdialysis probes incorporating an electrode were implanted intothe striatum of anaesthetised rats, repeated NMDA stimuli were applied throughthe probe, and the resulting depolarisation was recorded. Changes inextracellular KYNA were assessed by HPLC analysis of consecutive dialysatesamples. Ro 61‐8048 (42 or 100 mg/kg) markedly increased the dialysate levelsof KYNA. The maximum increase (from 3.0 ± 1.0 to 31.0 ± 6.0nM; means ± SEM, n = 6) was observed 4 h after administrationof 100 mg/kg Ro 61‐8048, but the magnitude of the NMDA‐induced depolarisationswas not reduced. A separate study suggested that extracellular KYNA would needto be increased further by two orders of magnitude to become effective in thispreparation. These results challenge the notion that kynurenine 3‐hydroxylaseinhibition may be neuroprotective, primarily through accumulation of KYNA andsubsequent attenuation of NMDA receptor function. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Neurochemistry Wiley

Kynurenine 3‐Hydroxylase Inhibition in Rats

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References (48)

Publisher
Wiley
Copyright
Copyright © 2000 Wiley Subscription Services
ISSN
0022-3042
eISSN
1471-4159
DOI
10.1046/j.1471-4159.2000.0752427.x
Publisher site
See Article on Publisher Site

Abstract

Abstract: Inhibition of kynurenine 3‐hydroxylase suppressesquinolinic acid synthesis and, therefore, shunts all kynurenine metabolismtoward kynurenic acid (KYNA) formation. This may be a pertinentantiexcitotoxic strategy because quinolinic acid is an agonist of NMDAreceptors, whereas kynurenic acid antagonises all ionotropic glutamatereceptors with preferential affinity for the NMDA receptor glycine site. Wehave examined whether the kynurenine 3‐hydroxylase inhibitor Ro 61‐8048increases extracellular (KYNA) sufficiently to control excessive NMDA receptorfunction. Microdialysis probes incorporating an electrode were implanted intothe striatum of anaesthetised rats, repeated NMDA stimuli were applied throughthe probe, and the resulting depolarisation was recorded. Changes inextracellular KYNA were assessed by HPLC analysis of consecutive dialysatesamples. Ro 61‐8048 (42 or 100 mg/kg) markedly increased the dialysate levelsof KYNA. The maximum increase (from 3.0 ± 1.0 to 31.0 ± 6.0nM; means ± SEM, n = 6) was observed 4 h after administrationof 100 mg/kg Ro 61‐8048, but the magnitude of the NMDA‐induced depolarisationswas not reduced. A separate study suggested that extracellular KYNA would needto be increased further by two orders of magnitude to become effective in thispreparation. These results challenge the notion that kynurenine 3‐hydroxylaseinhibition may be neuroprotective, primarily through accumulation of KYNA andsubsequent attenuation of NMDA receptor function.

Journal

Journal of NeurochemistryWiley

Published: Jan 1, 2000

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