Metabolism of [5‐³H]Kynurenine in the Rat Brain In Vivo: Evidence for the Existence of a Functional Kynurenine Pathway

Abstract

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 'U'M [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 ItM [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 .2fold) 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 .

Tetrahydrobiopterin Biosynthesis as a Potential Target of the Kynurenine Pathway Metabolite Xanthurenic Acid

“…It is not known whether xanthurenic acid distributes evenly or is concentrated in specific cell types in these brain regions; thus local concentrations of xanthurenic acid could be higher than 1 M. Up-regulation of the kynurenine pathway can also result in increased xanthurenic acid concentrations. Indeed, increased metabolism of kynurenine to xanthurenic acid was demonstrated in quinolinic acid-lesioned rat striata (27). In summary, the inhibitory activity of xanthurenic acid presented here for SPR and its reported concentrations in vivo suggest that it could inhibit BH 4 synthesis in vivo.…”

Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

“…In the brain, both QUIN and KYNA are derived from KYN, which enters the CNS via the same carrier system as tryptophan (Fukui et al, 1991;Guidetti et al, 1995). However, unlike tryptophan, which serves as a substrate for serotonin biosynthesis in neurons, brain KYN is preferentially metabolized in astrocytes and microglial cells.…”

Manipulation of Brain Kynurenines: Glial Targets, Neuronal Effects, and Clinical Opportunities

“…Immunocytochemical and lesion studies, as well as experiments with primary cell cultures, have provided additional information regarding the cellular localization of KP enzymes (Guidetti et al, 1995;Heyes et al, 1996;Guillemin et al, 2001). Most of this work was designed to identify the cellular and subcellular source of QUIN and KYNA in cerebral tissue and revealed unequivocally that glial cells, rather than neurons, harbor the enzymatic machinery for the biosynthesis of brain kynurenines.…”

“…Thus, the levels of brain kynurenines are often abnormal as a result of pathogenic events (see Stone, 2001, for a recent review). In essence, cerebral KP metabolism is always stimulated in response to focal physical injury, resulting in the rapid up-regulation of QUIN, 3-HK, and KYNA formation (Guidetti et al, 1995). This reaction is due to the activation of glial cells and can often be observed for days and weeks after an insult.…”