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*INSERM U-575 and Department of Biochemistry, Faculty of Medicine, Strasbourg, France CEA/Saclay, Department d’Inge´nierie et d’Etudes des prote´ines, Gif Sur Yvette, FranceThe kynurenine pathway is the principal metabolic route forcatabolism of tryptophan. Several intermediates of the path-way are active at central neurotransmitter sites, for example,the NMDA receptor agonist quinolinic acid and the gluta-mate receptor antagonist kynurenic acid. The latter is mainlysynthesized in rat brain astrocytes by kynurenine aminotrans-ferase and is released into the immediate vicinity of gluta-matergic synapses to possibly reduce the neurotoxic effectsof excitatory amino acid (Guidetti et al. 1995, 2007; Ceresoliet al. 1997). These findings raised the possibility that thekynurenine pathway and the metabolites of tryptophan couldbe involved in various neuroregulatory and neuropatholo-gical phenomenon in the CNS (Stone and Darlington 2002).Xanthurenic acid (Xa) is one metabolite of this kynureninepathway and could be considered as the parent compound ofkynurenic acid. Indoleamine 2,3 dioxygenase which ispresent in the brain transforms tryptophan into kynureninethat is either transaminated into kynurenic acid by kynure-nine aminotransferase or hydroxylated into 3-hydroxykynur-enine by kynurenine 3-hydroxylase. Transamination of3-hydroxykynurenine leads to xanthurenic acid (Fig. 1).The latter pathway is generally considered to be part of adetoxification process that reduces the concentration of 3-hydroxykynurenine because spontaneous oxidation of thissubstance induces free radical generation and apoptosis, bothin vitro and in vivo (Okuda et al. 1996; Wei et al. 2000).However, a transaminase specific for 3-hydroxykynureninehas not been identified in man. In mammals, it is generallythought that 3-hydroxykynurenine is transformed to Xa bythe same kynurenine transaminase isoenzymes that catalyzethe transamination of kynurenine to kynurenic acid (Urenjakand Obrenovitch 2000).

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- 3 H]KYN in vivo. The time course of metabolite accumulation was examined 15 min to 4 h after injection of [5- 3 H]KYN, and the concentration dependence of KYN metabolism was studied in rats killed 2 h after injection of 1.5-1,500 μM [5- 3 H]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 μM [5- 3 H]-KYN, a lesion-induced increase in KYN metabolism was noted. Thus, the proportional recoveries of [ 3 H]KYNA (5.0 vs. 1.8%), [ 3 H]3-HK (20.9 vs. 4.5%), [ 3 H]XA (1.5 vs. 0.4%), and [ 3 H]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.