Metabolism of [5-3H]kynurenine in the rat brain in vivo: evidence for the existence of a functional kynurenine pathway.
The incorporation of tritium-label into quinolinic acid (QUIN), kynurenic acid (KYNA), and other kynurenine (KYN) pathway metabolites was studied in normal and QUIN-lesioned rat striata after a focal injection of [5-3H]KYN in vivo. The time course of metabolite accumulation was examined 15 min to 4 h after injection of [5-3H]KYN, and the concentration dependence of KYN metabolism was studied in rats killed 2 h after injection of 1.5-1,500 microM [5-3H]KYN. Labeled QUIN, KYNA, 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid, and xanthurenic acid (XA) were recovered from the striatum in every experiment. Following injection of 15 microM [5-3H]KYN, a lesion-induced increase in KYN metabolism was noted. Thus, the proportional recoveries of [3H]KYNA (5.0 vs. 1.8%), [3H]3-HK (20.9 vs. 4.5%), [3H]XA (1.5 vs. 0.4%), and [3H]QUIN (3.6 vs. 0.6%) were markedly elevated in the lesioned striatum. Increases in KYN metabolism in lesioned tissue were evident at all time points and KYN concentrations used. Lesion-induced increases of the activities of kynurenine-3-hydroxylase (3.6-fold), kynureninase (7.6-fold), kynurenine aminotransferase (1.8-fold), and 3-hydroxyanthranilic acid oxygenase (4.2-fold) likely contributed to the enhanced flux through the pathway in the lesioned striatum. These data provide evidence for the existence of a functional KYN pathway in the normal rat brain and for a substantial increase in flux after neuronal ablation. This method should be of value for in vivo studies of cerebral KYN pathway function and dysfunction.
Guidetti
P
P
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore 21228, USA.
Eastman
C L
CL
Schwarcz
R
R
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006867:Hydrolases / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009994:Osmolar Concentration; D017378:Quinolinic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014316:Tritium
D014316:Tritium; D007737:Kynurenine; D006899:Mixed Function Oxygenases; D050601:Kynurenine 3-Monooxygenase; D006867:Hydrolases; C021480:kynureninase; D017378:Quinolinic Acid