Kynurenine 3‐Hydroxylase Inhibition in Rats

Abstract

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 Ϯ 1.0 to 31.0 Ϯ 6.0 nM; means Ϯ SEM, n ϭ 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. Key Words: Excitotoxicity-Kynurenine 3-hydroxylaseKynurenic acid-Microdialysis-Ro 61-8048 -N-Methyl-D-aspartate receptor.

Prenatal inhibition of the kynurenine pathway leads to structural changes in the hippocampus of adult rat offspring

“…When Ro61-8048 and other KMO inhibitors are administered to adult animals, their major effect is to increase the levels of kynurenic acid in the blood and tissues (Chiarugi et al ., 1995 ; Speciale et al ., 1996 ; Röver et al ., 1997 ; Cozzi et al ., 1999 ; Clark et al ., 2005 ), including at least 10-fold elevations in brain microdialysates in vivo (Urenjak & Obrenovitch, 2000 ) In the present study, Ro61-8048 was administered to pregnant rats at a dose that has been shown to increase kynurenic acid levels in the blood and brain of the pregnant dam and the brains of the embryos. An increase of 10–100-fold was produced after 5 h in utero ; the level returned to the control value in the mother after 24 h, but remained little changed in the embryos (Forrest et al ., 2013a ).…”

KYNA analogue SZR72 modifies CFA-induced dural inflammation- regarding expression of pERK1/2 and IL-1β in the rat trigeminal ganglion

“…Astrocytes represent one source of neuroprotective KYNA [ 6 , 20 ]; KYNA was presumed to have protective effect in neuronal cell death [ 21 , 22 ]. Studies have also suggested that an elevated extracellular KYNA level would be needed to act more effectively [ 23 ], leading to the idea of systemic administration of KYNA. This was not proved to be an ideal therapeutic option, as KYNA poorly penetrates the blood-brain barrier and it undergoes a rapid clearance from the brain and the circulation [ 24 ].…”

Chronic Glutamate Toxicity in Neurodegenerative Diseases—What is the Evidence?

“…KYNA was reported to act as an NMDA receptor antagonist (Ganong et al, 1983 ; Ganong and Cotman, 1986 ). However, although infusion with the KMO inhibitor Ro 61-8048 increased cerebral extracellular KYNA concentrations 10-fold, this did not lead to an inhibition of NMDA-mediated neuronal depolarization, a finding that challenges the notion that KYNA at near physiological levels directly modulates NMDA receptors (Urenjak and Obrenovitch, 2000 ). In contrast, increased KYNA in the brain induced by the KMO inhibitor JM6 decreased the extracellular cerebral L-glu concentration (Zwilling et al, 2011 ).…”