Quinolinic acid (abbreviated QUIN or QA), also known as pyridine-2,3-dicarboxylic acid, is a dicarboxylic acid with a pyridine backbone. It is a colorless solid. It is the biosynthetic precursor to niacin. Quinolinic acid is a downstream product of the kynurenine pathway, which metabolizes the amino acid tryptophan. It acts as an NMDA receptor agonist. Quinolinic acid has a potent neurotoxic effect. Studies have demonstrated that quinolinic acid may be involved in many psychiatric disorders, neurodegenerative processes in the brain, as well as other disorders. Within the brain, quinolinic acid is only produced by activated microglia and macrophages.
History In 1949 L. Henderson was one of the earliest to describe quinolinic acid. Lapin followed up this research by demonstrating that quinolinic acid could induce convulsions when injected into mice brain ventricles. However, it was not until 1981 that Stone and Perkins showed that quinolinic acid activates the N-methyl-d-aspartate receptor (NMDAR). After this, Schwarcz demonstrated that elevated quinolinic acid levels could lead to axonal neurodegeneration.
Synthesis One of the earliest reported syntheses of this quinolinic acid was by Zdenko Hans Skraup, who found that methyl-substituted quinolines could be oxidized to quinolinic acid by potassium permanganate. This compound is commercially available. It is generally obtained by the oxidation of quinoline. Oxidants such as ozone, hydrogen peroxide, and potassium permanganate have been used. Electrolysis is able to perform the transformation as well. Quinolinic acid may undergo further decarboxylation to nicotinic acid (a precursor to niacin):
Biosynthesis
From aspartate Oxidation of aspartate by the enzyme L-aspartate oxidase gives iminosuccinic acid, containing the two carboxylic acid groups that are found in quinolinic acid. Condensation of iminosuccinic acid with dihydroxyacetone phosphate, mediated by quinolinate synthase, affords quinolinic acid.
Catabolism of tryptophan
Quinolinic acid is a byproduct of the kynurenine pathway, which is responsible for catabolism of tryptophan in mammals. This pathway is important for its production of the coenzyme nicotinamide adenine dinucleotide (NAD+) and produces several neuroactive intermediates including quinolinic acid, kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and 3-hydroxyanthranilic acid (3-HANA). Quinolinic acid's neuroactive and excitatory properties are a result of NMDA receptor agonism in the brain. It also acts as a neurotoxin, gliotoxin, proinflammatory mediator, and pro-oxidant molecule. While quinolinic acid cannot pass the BBB, kynurenine, tryptophan and 3-hydroxykynurenine do and subsequently act as precursors to the production of quinolinic acid in the brain. The quinolinic acid produced in microglia is then released and stimulates NMDA receptors, resulting in excitatory neurotoxicity. While astrocytes do not produce quinolinic acid directly, they do produce KYNA, which when released from the astrocytes can be taken in by migroglia that can in turn increase quinolinic acid production. Microglia and macrophages produce the vast majority of quinolinic acid present in the body. This production increases during an immune response. It is suspected that this is a result of activation of indoleamine dioxygenases (to be specific, IDO-1 and IDO-2) as well as tryptophan 2,3-dioxygenase (TDO) stimulation by inflammatory cytokines (mainly IFN-gamma, but also IFN-beta and IFN-alpha). IDO-1, IDO-2 and TDO are present in microglia and macrophages. Under inflammatory conditions and conditions of T cell activation, leukocytes are retained in the brain by cytokine and chemokine production, which can lead to the breakdown of the BBB, thus increasing the quinolinic acid that enters the brain. Furthermore, quinolinic acid has been shown to play a role in destabilization of the cytoskeleton within astrocytes and brain endothelial cells, contributing to the degradation of the BBB, which results in higher concentrations of quinolinic acid in the brain.
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