The Complex World of Kynurenic Acid: Reflections on Biological Issues and Therapeutic Strategy

Abstract

It has been unequivocally established that kynurenic acid has a number of actions in a variety of cells and tissues, raising, in principle, the possibility of targeting its generation, metabolism or sites of action to manipulate those effects to a beneficial therapeutic end. However, many basic aspects of the biology of kynurenic acid remain unclear, potentially leading to some confusion and misinterpretations of data. They include questions of the source, generation, targets, enzyme expression, endogenous concentrations and sites of action. This essay is intended to raise and discuss many of these aspects as a source of reference for more balanced discussion. Those issues are followed by examples of situations in which modulating and correcting kynurenic acid production or activity could bring significant therapeutic benefit, including neurological and psychiatric conditions, inflammatory diseases and cell protection. More information is required to obtain a clear overall view of the pharmacological environment relevant to kynurenic acid, especially with respect to the active concentrations of kynurenine metabolites in vivo and changed levels in disease. The data and ideas presented here should permit a greater confidence in appreciating the sites of action and interaction of kynurenic acid under different local conditions and pathologies, enhancing our understanding of kynurenic acid itself and the many clinical conditions in which manipulating its pharmacology could be of clinical value.

Keywords: AHR; AMPA; GPR35; NMDA; aryl hydrocarbon receptors; glutamate; hydroxy-carboxylic acid receptors; kynurenine; tryptophan.

Figure 2

Kynurenic acid: main sites of action. A summary of the major targets responsible for the actions of kynurenic acid is provided here. In the CNS, glutamate—as the dominant excitatory neurotransmitter—acts on ionotropic receptors characterised by their sensitivity to NMDA, AMPA or kainate. Kynurenic acid blocks all three receptors on postsynaptic neurons, but has its greatest effect on NMDA receptors where it blocks the glutamate binding site on the GluN2 subunit, and the (strychnine-resistant) glycine-B co-agonist site located on GluN1. In contrast, kynurenic acid is an agonist at the GPR35 protein, where it has been reported to inhibit neuronal activity and glial function. Kynurenic acid is generated in neurons and glia and also gains entry from the systemic circulation by passive diffusion and active transport across the blood–brain barrier by LAT-1 and OATs. In immune system cells, kynurenine and kynurenic acid are produced by the activation of IDO1/2 or TDO in myeloid cells and tolerogenic dendritic cells. Kynurenic acid then activates AHRs, which promote the differentiation of naïve CD4+ T cells to regulatory T cells (Tregs) via the induced expression of FoxP3, and inhibits differentiation to IL-17-producing cells. The production of kynurenic acid is maintained by a positive feedback cycle via the AHR-induced expression of IL-6 which then induces further IDO1. IDO activity is also maintained and regulated by TGF-β released from activated macrophages, by Cytotoxic Lymphocyte Antigen-4 (CTLA-4), and by the Glucose-Induced TNF Receptor-Related Ligand (GITR-L). The activation of GPR35 in leucocytes inhibits their production of inflammatory mediators such as IFN-γ, IL-1β, IL-6 and TNFα.

Figure 1

Synthesis and sources of kynurenic acid. A summary of the synthetic pathway for kynurenic acid. The dominant enzymes IDO1 and IDO2 are in the tissues, and TDO in the liver. Tryptophan is present in the GiT and in dietary foods, and is synthesised from anthranilic acid in bacteria. The amino acid and its metabolites in the GiT, including components of the kynurenine pathway, readily enter the host circulation and tissues. The enzyme IL4i1 in tissues metabolises tryptophan directly to simple indole compounds including indolacetate, indole-3-propionate and indole-3-pyruvic acid. The later then spontaneously cyclizes to kynurenic acid. Trp: tryptophan; AFMID: arylformamidase; 3-HK: 3-hydroxykynurenine; 3-HAA: 3-hydroxyanthranilic acid; 3-HAO: 3-hydroxyanthranilic acid oxygenase; QPRT: quinolinate phosphoribosyltransferase; AA, anthranilic acid.