Quinolinic acid
Quinolinic acid, 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--aspartate receptor. 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 :
Biosynthesis
From aspartate
Oxidation of aspartate by the enzyme aspartate oxidase gives iminosuccinate, containing the two carboxylic acid groups that are found in quinolinic acid. Condensation of iminosuccinate with glyceraldehyde-3-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 and produces several neuroactive intermediates including quinolinic acid, kynurenine, kynurenic acid, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid. 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 as well as tryptophan 2,3-dioxygenase stimulation by inflammatory cytokines.
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.
Toxicity
Quinolinic acid is an excitotoxin in the CNS. It reaches pathological levels in response to inflammation in the brain, which activates resident microglia and macrophages. High levels of quinolinic acid can lead to hindered neuronal function or even apoptotic death. Quinolinic acid produces its toxic effect through several mechanisms, primarily as its function as an NMDA receptor agonist, which triggers a chain of deleterious effects, but also through lipid peroxidation, and cytoskeletal destabilization. The gliotoxic effects of quinolinic acid further amplify the inflammatory response. Quinolinic acid affects neurons located mainly in the hippocampus, striatum, and neocortex, due to the selectivity toward quinolinic acid by the specific NMDA receptors residing in those regions.When inflammation occurs, quinolinic acid is produced in excessive levels through the kynurenine pathway. This leads to over excitation of the NMDA receptor, which results in an influx of Ca2+ into the neuron. High levels of Ca2+ in the neuron trigger an activation of destructive enzymatic pathways including protein kinases, phospholipases, NO synthase, and proteases. These enzymes will degenerate crucial proteins in the cell and increase NO levels, leading to an apoptotic response by the cell, which results in cell death.
In normal cell conditions, astrocytes in the neuron will provide a glutamate–glutamine cycle, which results in reuptake of glutamate from the synapse into the pre-synaptic cell to be recycled, keeping glutamate from accumulating to lethal levels inside the synapse. At high concentrations, quinolinic acid inhibits glutamine synthetase, a critical enzyme in the glutamate–glutamine cycle. In addition, It can also promote glutamate release and block its reuptake by astrocytes. All three of these actions result in increased levels of glutamate activity that could be neurotoxic.
This results in a loss of function of the cycle, and results in an accumulation of glutamate. This glutamate further stimulates the NMDA receptors, thus acting synergistically with quinolinic acid to increase its neurotoxic effect by increasing the levels of glutamate, as well as inhibiting its uptake. In this way, quinolinic acid self-potentiates its own toxicity. Furthermore, quinolinic acid results in changes of the biochemistry and structure of the astrocytes themselves, resulting in an apoptotic response. A loss of astrocytes results in a pro-inflammatory effect, further increasing the initial inflammatory response which initiates quinolinic acid production.
Quinolinic acid can also exert neurotoxicity through lipid peroxidation, as a result of its pro-oxidant properties. Quinolinic acid can interact with Fe to form a complex that induces a reactive oxygen and nitrogen species, notably the hydroxyl radical •OH. This free radical causes oxidative stress by further increasing glutamate release and inhibiting its reuptake, and results in the breakdown of DNA in addition to lipid peroxidation.
Quinolinic acid has also been noted to increase phosphorylation of proteins involved in cell structure, leading to destabilization of the cytoskeleton.
Clinical implications
Psychiatric disorders
Mood disorders
The prefrontal cortices in the post-mortem brains of patients with major depression and bipolar depression contain increased quinolinic acid immunoreactivity compared to the brains of patients never having had depression. The fact that NMDA receptor antagonists possess antidepressant properties suggests that increased levels of quinolinic acid in patients with depression may overactivate NMDA receptors. By inducing increased levels of quinolinic acid in the cerebral spinal fluid with interferon α, researchers have demonstrated that increased quinolinic acid levels correlate with increased depressive symptoms.Increased levels of quinolinic acid might contribute to the apoptosis of astrocytes and certain neurons, resulting in decreased synthesis of neurotrophic factors. With less neurotrophic factors, the astrocyte-microglia-neuronal network is weaker and thus is more likely to be affected by environmental factors such as stress. In addition, increased levels of quinolinic acid could play a role in impairment of the glial-neuronal network, which could be associated with the recurrent and chronic nature of depression.
Furthermore, studies have shown that unpredictable chronic mild stress can lead to the metabolism of quinolinic acid in the amygdala and striatum and a reduction in quinolinic acid pathway in the cingulate cortex. Experiments with mice demonstrate how quinolinic acid can affect behavior and act as endogenous anxiogens. For instance, when quinolinic acid levels are increased, mice socialize and groom for shorter periods of time. There is also evidence that increased concentrations of quinolinic acid can play a role in adolescent depression.