Metabolism and neuropathologic significance of quinolinic acid and kynurenic acid.

Neurologic symptoms and neurodegeneration are important causes of morbidity and mortality in man. Although many pathogenic mechanisms could account for neurologic dysfunction, considerable interest has focused on a group of neurotoxins known as the ‘excitotoxins’. Quinolinic acid (QUIN) is an excitotoxic L-tryptophan and kynurenine pathway metabolite that is an agonist of N-methyl-uaspartate (NMDA) receptors (Figure 1) [l-31. The related metabolite, kynurenic acid (KYNA), is an antagonist of NMDA and other excitatory amino acid receptors that may protect against excitotoxins [4, 51. KYNA also induces neurologic dysfunction by interfering with excitatory amino acid neurotransmission [6]. Therefore, disturbances in the concentrations of QUIN and KYNA within the brain may have neurologic and neuropathologic consequences. An understanding of the sources of kynurenine pathway metabolites in blood and central nervous system (CNS) is incomplete. One contemporary model has been derived from studies in normal rats. The liver is viewed as the predominant source of kynurenine pathway metabolites [7], and has been suggested as the only source of QUIN in the body [S]. KYNA originates from L-kynurenine [9-111, which is synthesized in brain or enters the CNS from the blood [12-141. QUIN is not synthesized from L-tryptophan or 1,-kynurenine in the normal brain [ 151, but originates from blood-derived precursors [ 141, particularly anthranilic acid [ 161. QUIN is synthesized within the CNS from 3hydroxyanthranilic acid via 3-hydroxyanthranilate3,4-dioxygenase localized in astrocytes [ 17, 181. A significantly different picture of how QUIN and KYNA are metabolized has emerged from studies of the consequences of immune activation. This review will summarize these responses.