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| Names | |
|---|---|
| Preferred IUPAC name Pyridine-2,3-dicarboxylic acid | |
| Other names 2,3-Pyridinedicarboxylic acid | |
| Identifiers | |
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3D model (JSmol) | |
| ChEBI | |
| ChEMBL | |
| ChemSpider |
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| ECHA InfoCard | 100.001.704 |
| EC Number |
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| KEGG |
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| MeSH | D017378 |
| UNII | |
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| Properties | |
| C7H5NO4 | |
| Molar mass | 167.12 g/mol |
| Melting point | 185 to 190 °C (365 to 374 °F; 458 to 463 K) (decomposes) |
| Hazards | |
| Safety data sheet (SDS) | External MSDS |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Quinolinic acid (abbreviatedQUIN orQA), also known as pyridine-2,3-dicarboxylic acid, is adicarboxylic acid with apyridine backbone. It is a colorlesssolid. It is the biosyntheticprecursor toniacin.[1]
Quinolinic acid is adownstream product of thekynurenine pathway, whichmetabolizes theamino acidtryptophan. It acts as anNMDA receptoragonist.[2]
Quinolinic acid has a potentneurotoxic effect. Studies have demonstrated that quinolinic acid may be involved in manypsychiatric disorders,neurodegenerative processes in thebrain, as well as other disorders. Within the brain, quinolinic acid is only produced by activatedmicroglia andmacrophages.[3]
In 1949 L. Henderson was one of the earliest to describe quinolinic acid. Lapin followed up this research by demonstrating that quinolinic acid could induceconvulsions when injected into micebrain ventricles. However, it was not until 1981 that Stone and Perkins showed that quinolinic acid activates theN-methyl-D-aspartate receptor (NMDAR). After this, Schwarcz demonstrated that elevated quinolinic acid levels could lead toaxonalneurodegeneration.[4]
One of the earliest reported syntheses of this quinolinic acid was byZdenko Hans Skraup, who found thatmethyl-substitutedquinolines could beoxidized to quinolinic acid by potassium permanganate.[5]
This compound is commercially available. It is generally obtained by the oxidation of quinoline.Oxidants such asozone,[6]hydrogen peroxide,[7] andpotassium permanganate have been used. Electrolysis is able to perform the transformation as well.[8][9]
Quinolinic acid may undergo furtherdecarboxylation to nicotinic acid (a precursor toniacin):
Oxidation ofaspartate by theenzyme aspartate oxidase givesiminosuccinate, containing the twocarboxylic acid groups that are found in quinolinic acid.Condensation of iminosuccinate withglyceraldehyde-3-phosphate, mediated byquinolinate synthase, affords quinolinic acid.[1]
Quinolinic acid is abyproduct of thekynurenine pathway, which is responsible forcatabolism of tryptophan inmammals. This pathway is important for its production of thecoenzymenicotinamide adenine dinucleotide (NAD+) and produces severalneuroactiveintermediates including quinolinic acid,kynurenine (KYN),kynurenic acid (KYNA),3-hydroxykynurenine (3-HK), and3-hydroxyanthranilic acid (3-HANA).[10][11] Quinolinic acid's neuroactive and excitatory properties are a result ofNMDA receptor agonism in the brain.[11] It also acts as aneurotoxin, gliotoxin, proinflammatory mediator, and pro-oxidant molecule.[10]
While quinolinic acid cannot pass the BBB, kynurenine,[12] tryptophan and 3-hydroxykynurenine do and subsequently act as precursors to the production of quinolinic acid in the brain. The quinolinic acid produced inmicroglia is then released and stimulatesNMDA receptors, resulting in excitatory neurotoxicity.[11] Whileastrocytes 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.[10][11]
Microglia and macrophages produce the vast majority of quinolinic acid present in the body. This production increases during animmune response. It is suspected that this is a result of activation ofindoleamine dioxygenases (to be specific, IDO-1 and IDO-2) as well astryptophan 2,3-dioxygenase (TDO) stimulation byinflammatorycytokines (mainlyIFN-gamma, but also IFN-beta and IFN-alpha).[10]
IDO-1, IDO-2 and TDO are present in microglia and macrophages. Under inflammatory conditions and conditions ofT cell activation,leukocytes are retained in the brain by cytokine andchemokine 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 thecytoskeleton within astrocytes and brainendothelial cells, contributing to the degradation of the BBB, which results in higherconcentrations of quinolinic acid in the brain.[13]
Quinolinic acid is anexcitotoxin in theCNS. 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 hinderedneuronal function or evenapoptotic death.[10] 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 throughlipid peroxidation, and cytoskeletal destabilization.[10] The gliotoxic effects of quinolinic acid further amplify the inflammatory response. Quinolinic acid affects neurons located mainly in thehippocampus,striatum, andneocortex, due to the selectivity toward quinolinic acid by the specific NMDA receptors residing in those regions.[10]
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 ofCa2+ into the neuron. High levels of Ca2+ in the neuron trigger an activation of destructive enzymatic pathways includingprotein kinases,phospholipases,NO synthase, andproteases.[14] 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 aglutamate–glutamine cycle, which results inreuptake ofglutamate from thesynapse into the pre-synaptic cell to be recycled, keeping glutamate from accumulating to lethal levels inside the synapse. At high concentrations, quinolinic acidinhibitsglutamine 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.[10]
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 actingsynergistically 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.[10] 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.[10]
Quinolinic acid can also exert neurotoxicity through lipid peroxidation, as a result of itspro-oxidant properties. Quinolinic acid can interact with Fe(II) to form a complex that induces a reactive oxygen and nitrogen species (ROS/RNS), notably the hydroxyl radical •OH. This free radical causesoxidative stress by further increasing glutamate release and inhibiting its reuptake, and results in the breakdown ofDNA in addition to lipid peroxidation.[14]Quinolinic acid has also been noted to increase phosphorylation of proteins involved in cell structure, leading to destabilization of thecytoskeleton.[10]
Theprefrontal cortices in thepost-mortem brains of patients withmajor depression andbipolar depression contain increased quinolinic acidimmunoreactivity compared to the brains of patients never having had depression.[15] The fact thatNMDA receptorantagonists possessantidepressant properties suggests that increased levels of quinolinic acid in patients with depression may overactivate NMDA receptors.[11] By inducing increased levels of quinolinic acid in thecerebral spinal fluid withinterferon α, researchers have demonstrated that increased quinolinic acid levels correlate with increased depressive symptoms.[16]
Increased levels of quinolinic acid might contribute to theapoptosis ofastrocytes and certain neurons, resulting in decreased synthesis ofneurotrophic 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 theglial-neuronal network, which could be associated with the recurrent and chronic nature of depression.[15]
Furthermore, studies have shown thatunpredictable chronic mild stress (UCMS) can lead to themetabolism of quinolinic acid in theamygdala andstriatum and a reduction in quinolinic acid pathway in thecingulate cortex. Experiments with mice demonstrate how quinolinic acid can affect behavior and act asendogenousanxiogens. For instance, when quinolinic acid levels are increased, mice socialize and groom for shorter periods of time.[16] There is also evidence that increased concentrations of quinolinic acid can play a role inadolescent depression.[15]
Quinolinic acid may be involved inschizophrenia; however, there has been no research done to examine the specific effects of quinolinic acid in schizophrenia. There are many studies that show thatkynurenic acid (KYNA) plays a role in the positive symptoms of schizophrenia, and there has been some research to suggest that3-hydroxykynurenine (OHK) plays a role in the disease as well. Because quinolinic acid is strongly associated with KYNA and OHK, it may too play a role in schizophrenia.[11][15]
Thecytotoxic effects of quinolinic acid elaborated upon in the toxicity section amplify cell death inneurodegenerative conditions.
Quinolinic acid may contribute to the causes ofamyotrophic lateral sclerosis (ALS). Researchers have found elevated levels of quinolinic acid in thecerebral spinal fluid (CSF),motor cortex, andspinal cord in ALS patients. These increased concentrations of quinolinic acid could lead toneurotoxicity. In addition, quinolinic acid is associated with overstimulating NMDA receptors on motor neurons. Studies have demonstrated that quinolinic acid leads to depolarization of spinalmotor neurons by interacting with the NMDA receptors on those cells in rats. Also, quinolinic acid plays a role inmitochondrial dysfunction in neurons. All of these effects could contribute to ALS symptoms.[17]
Researchers have found a correlation between quinolinic acid andAlzheimer's disease. For example, studies have found in the post-mortem brains of Alzheimer's disease patients higher neuronal quinolinic acid levels and that quinolinic acid can associate withtau protein.[11][18] Furthermore, researchers have demonstrated that quinolinic acid increases tauphosphorylationin vitro in humanfetal neurons[11][18] and induces ten neuronalgenes including some known to correlate with Alzheimer's disease.[18] Inimmunoreactivity studies, researchers have found that quinolinic acid immunoreactivity is strongest inglial cells that are located close toamyloid plaques and that there is immunoreactivity withneurofibrillary tangles.[11]
Brain ischemia is characterized by insufficientblood flow to the brain. Studies with ischaemic gerbils indicate that, after a delay, levels of quinolinic acid significantly increase, which correlates with increased neuronal damage.[15][19] In addition, researchers have found that, after transient global ischaemia, there aremicroglia containing quinolinic acid within the brain. Following cerebral ischaemia, delayed neuronal death may occur in part because of central microglia andmacrophages, which possess and secrete quinolinic acid. This delayed neurodegeneration could be associated with chronic brain damage that follows astroke.[19]
Studies have found that there is a correlation between levels of quinolinic acid in cerebral spinal fluid (CSF) andHIV-associated neurocognitive disorder (HAND) severity. About 20% ofHIV patients have this disorder. Concentrations of quinolinic acid in the CSF are associated to different stages of HAND. For example, raised levels of quinolinic acid after infection are correlated to perceptual-motor slowing in patients. Then, in later stages of HIV, increased concentrations of quinolinic acid in the CSF of HAND patients correlates with HIVencephalitis andcerebral atrophy.[20]
Quinolinic acid has also been found in HAND patients' brains. In fact, the amount of quinolinic acid found in the brain of HAND patients can be up to 300 times greater than that found in the CSF.[21] Neurons exposed to quinolinic acid for long periods of time can developcytoskeletal abnormalities,vacuolization, and cell death. HAND patients' brains contain many of these defects. Furthermore, studies in rats have demonstrated that quinolinic acid can lead toneuronal death in brains structures that are affected by HAND, including thestriatum,hippocampus, thesubstantia nigra, and non-limbiccortex.[20]
Levels of quinolinic acid in the CSF ofAIDS patients withAIDS- dementia can be up to twenty times higher than normal. Similar to HIV patients, this increased quinolinic acid concentration correlates with cognitive and motor dysfunction. When patients were treated withzidovudine to decrease quinolinic acid levels, the amount of neurological improvement was related to the amount of quinolinic acid decreased.[21]
In the initial stages ofHuntington's disease, patients have substantially increased quinolinic acid levels, in particular in the neostriatum andcortex. These areas of the brain that had the most damage at these stages.[17][19] The increase in quinolinic acid correlates with the early activation ofmicroglia and increasedcerebral3-hydroxykynurenine (3-HK) levels. Furthermore, these increased levels of quinolinic acid are great enough to produceexcitotoxic neuronal damage.[11] Studies have demonstrated that activation ofNMDA receptors by quinolinic acid leads to neuronal dysfunction and death ofstriatalGABAergicmedium spiny neurons (MSN).[17]
Researchers utilize quinolinic acid in order to study Huntington's disease in many model organisms. Because injection of quinolinic acid into thestriatum of rodents induces electrophysiological, neuropathological, and behavioral changes similar to those found in Huntington's disease, this is the most common method researchers use to produce a Huntington's diseasephenotype.[15][19] Neurological changes produced by quinolinic acid injections include altered levels ofglutamate,GABA, and otheramino acids.Lesions in thepallidum can suppress effects of quinolinic acid in monkeys injected with quinolinic acid into their striatum. In humans, such lesions can also diminish some of the effects of Huntington's disease andParkinson's disease.[21]
Quinolinic acid neurotoxicity is thought to play a role inParkinson's disease.[17][22] Studies show that quinolinic acid is involved in the degeneration of thedopaminergic neurons in thesubstantia nigra (SN) of Parkinson's disease patients. SN degeneration is one of the key characteristics of Parkinson's disease. Microglia associated with dopaminergic cells in the SN produce quinolinic acid at this location when scientists induce Parkinson's disease symptoms inmacaques. Quinolinic acid levels are too high at these sites to be controlled by KYNA, causing neurotoxicity to occur.[17]
Quinolinic acid levels are increased in the brains of children infected with a range ofbacterial infections of the central nervous system (CNS),[19][21] ofpoliovirus patients,[21] and ofLyme disease withCNS involvement patients.[15][21] In addition, raised quinolinic acid levels have been found in traumatic CNS injury patients, patients with cognitive decline with ageing,hyperammonaemia patients,hypoglycaemia patients, andsystemic lupus erythematosus patients. Also, it has been found that people withmalaria and patients witholivopontocerebellar atrophy have raised quinolinic acidmetabolism.[21]
Reduction of the excitotoxic effects of quinolinic acid is the subject of on-going research.NMDAr antagonists have been shown to provide protection tomotor neurons from excitotoxicity resulting from quinolinic acid production.[10] Kynurenic acid, another product of the kynurenine pathway acts as an NMDAreceptor antagonist.[23]
Kynurenic acid thus acts as aneuroprotectant, by reducing the dangerous over-activation of the NMDA receptors. Manipulation of the kynurenine pathway away from quinolinic acid and toward kynurenic acid is therefore a major therapeutic focus. Nicotinylalanine has been shown to be an inhibitor of kynurenine hydroxylase, which results in a decreased production of quinolinic acid, thus favoring kynurenic acid production.[23] This change in balance has the potential to reduce hyperexcitability, and thus excitotoxic damage produced from elevated levels of quinolinic acid.[23] Therapeutic efforts are also focusing onantioxidants, which have been shown to provide protection against the pro-oxidant properties of quinolinic acid.[10]
Norharmane suppresses the production of quinolinic acid,3-hydroxykynurenine andnitric oxide synthase, thereby acting as a neuroprotectant.[24]Natural phenols such ascatechin hydrate,curcumin, andepigallocatechin gallate reduce the neurotoxicity of quinolinic acid, via anti-oxidant and possibly calcium influx mechanisms.[25]COX-2 inhibitors, such aslicofelone have also demonstrated protective properties against the neurotoxic effects of quinolinic acid. COX-2 is upregulated in many neurotoxic disorders and is associated with increased ROS production. Inhibitors have demonstrated some evidence of efficacy in mental health disorders such asmajor depressive disorder,schizophrenia, andHuntington's disease.[23]
