Quinolinic acid

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Quinolinic acid
Names
Preferred IUPAC name
Pyridine-2,3-dicarboxylic acid
Other names
2,3-Pyridinedicarboxylic acid
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard
 100.001.704 Edit this at Wikidata
EC Number
  • 201-874-8
KEGG
MeSH D017378
UNII
  • InChI=1S/C7H5NO4/c9-6(10)4-2-1-3-8-5(4)7(11)12/h1-3H,(H,9,10)(H,11,12) ☒N
    Key: GJAWHXHKYYXBSV-UHFFFAOYSA-N ☒N
  • InChI=1/C7H5NO4/c9-6(10)4-2-1-3-8-5(4)7(11)12/h1-3H,(H,9,10)(H,11,12)
    Key: GJAWHXHKYYXBSV-UHFFFAOYAW
  • C1=CC(=C(N=C1)C(=O)O)C(=O)O
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 their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Quinolinic acid (abbreviated QUIN or QA), also known as pyridine-2,3-dicarboxylic acid, is a

niacin.[1]

Quinolinic acid is a

metabolizes the amino acid tryptophan. It acts as an NMDA receptor agonist.[2]

Quinolinic acid has a potent

macrophages.[3]

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

neurodegeneration.[4]

Synthesis

One of the earliest reported syntheses of this quinolinic acid was by

oxidized to quinolinic acid by potassium permanganate.[5]

This compound is commercially available. It is generally obtained by the oxidation of quinoline.

Oxidants such as ozone,[6] hydrogen peroxide,[7] and potassium permanganate have been used. Electrolysis is able to perform the transformation as well.[8][9]

Quinolinic acid may undergo further

niacin
):

Biosynthesis

From aspartate

Oxidation of

glyceraldehyde-3-phosphate, mediated by quinolinate synthase, affords quinolinic acid.[1]

Catabolism of tryptophan

The Kynurenine pathway, which connects quinolinic acid to tryptophan. The pathway is named for the first intermediate, Kynurenine, which is a precursor to kynurenic acid and 3-hydroxykynurenine.

Quinolinic acid is a

3-hydroxykynurenine (3-HK), and 3-hydroxyanthranilic acid (3-HANA).[10][11] Quinolinic acid's neuroactive and excitatory properties are a result of NMDA receptor agonism in the brain.[11] It also acts as a neurotoxin, gliotoxin, proinflammatory mediator, and pro-oxidant molecule.[10]

While quinolinic acid cannot pass the BBB, kynurenine,

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.[10][11]

Microglia and macrophages produce the vast majority of quinolinic acid present in the body. This production increases during an

IFN-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 of

concentrations of quinolinic acid in the brain.[13]

Toxicity

Quinolinic acid is an

neuronal function or even apoptotic 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 through lipid peroxidation, and cytoskeletal destabilization.[10] 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.[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 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.[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 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.[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 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.[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 its pro-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 causes oxidative stress by further increasing glutamate release and inhibiting its reuptake, and results in the breakdown of DNA 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 the cytoskeleton.[10]

Clinical implications

Psychiatric disorders

Mood disorders

The

interferon α, researchers have demonstrated that increased quinolinic acid levels correlate with increased depressive symptoms.[16]

Increased levels of quinolinic acid might contribute to the

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.[15]

Furthermore, studies have shown that

endogenous anxiogens. 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 in adolescent depression.[15]

Schizophrenia

Quinolinic acid may be involved in

3-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]

Conditions related to neuronal death

The

neurodegenerative
conditions.

Amyotrophic lateral sclerosis (ALS)

Quinolinic acid may contribute to the causes of

mitochondrial dysfunction in neurons. All of these effects could contribute to ALS symptoms.[17]

Alzheimer's disease

Researchers have found a correlation between quinolinic acid and

amyloid plaques and that there is immunoreactivity with neurofibrillary tangles.[11]

Brain ischemia

blood 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 are microglia containing quinolinic acid within the brain. Following cerebral ischaemia, delayed neuronal death may occur in part because of central microglia and macrophages, which possess and secrete quinolinic acid. This delayed neurodegeneration could be associated with chronic brain damage that follows a stroke.[19]

Human immunodeficiency virus (HIV) and Acquired immunodeficiency syndrome (AIDS)

Studies have found that there is a correlation between levels of quinolinic acid in cerebral spinal fluid (CSF) and

HIV 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 HIV encephalitis and cerebral 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 develop cytoskeletal abnormalities, vacuolization, and cell death. HAND patients' brains contain many of these defects. Furthermore, studies in rats have demonstrated that quinolinic acid can lead to neuronal death in brains structures that are affected by HAND, including the striatum, hippocampus, the substantia nigra, and non-limbic cortex.[20]

Levels of quinolinic acid in the CSF of

AIDS- 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 with zidovudine to decrease quinolinic acid levels, the amount of neurological improvement was related to the amount of quinolinic acid decreased.[21]

Huntington's disease

In the initial stages of

excitotoxic neuronal damage.[11] Studies have demonstrated that activation of NMDA receptors by quinolinic acid leads to neuronal dysfunction and death of striatal GABAergic medium 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 the

pallidum 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 and Parkinson's disease.[21]

Parkinson's disease

Quinolinic acid neurotoxicity is thought to play a role in

macaques. Quinolinic acid levels are too high at these sites to be controlled by KYNA, causing neurotoxicity to occur.[17]

Other

Quinolinic acid levels are increased in the brains of children infected with a range of

systemic lupus erythematosus patients. Also, it has been found that people with malaria and patients with olivopontocerebellar atrophy have raised quinolinic acid metabolism.[21]

Treatment focus

Reduction of the excitotoxic effects of quinolinic acid is the subject of on-going research.

NMDAr antagonists have been shown to provide protection to motor neurons from excitotoxicity resulting from quinolinic acid production.[10] Kynurenic acid, another product of the kynurenine pathway acts as an NMDA receptor antagonist.[23]

Kynurenic acid thus acts as a neuroprotectant, 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 on antioxidants, which have been shown to provide protection against the pro-oxidant properties of quinolinic acid.[10]

COX-2 inhibitors, such as licofelone 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 as major depressive disorder, schizophrenia, and Huntington's disease.[23]

See also

References

  1. ^ a b Hiroshi Ashihara, Alan Crozier, Atsushi Komamine "Nicotine Biosynthesis" in Plant Metabolism and Biotechnology, Tsubasa Shoji, Takashi Hashimoto Eds. Wiley-VCH, Weinheim, 2011. {{DOI: 10.1002/9781119991311.ch7}}
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  6. ^ WO 2010011134, H. Bruno, "Ozonolysis of Aromatics and/or Olefins" 
  7. ^ US Patent 4420616, Ikegami, Seishi & Hatano, Yoshihiro, "Oxidative process for the preparation of copper quinolinate", assigned to Yamamoto Kagaku Gosei KK 
  8. PMID 20282382
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  9. ^ EP 0159769, Toomey Jr., Joseph E., "Electrochemical oxidation of pyridine bases", assigned to Reilly Industries, Inc. 
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    PMID 22260426
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    PMID 10936623
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