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Quinolinic acid
Quinolinic acid
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 dicarboxylic acid with a pyridine backbone. It is a colorless solid. It is the biosynthetic precursor to niacin.[1]

Quinolinic acid is a downstream product of the kynurenine pathway, which metabolizes the amino acid tryptophan. It acts as an NMDA receptor agonist.[2]

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.[3]

History

[edit]

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.[4]

Synthesis

[edit]

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.[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 decarboxylation to nicotinic acid (a precursor to niacin):

Biosynthesis

[edit]

From aspartate

[edit]

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.[1]

Catabolism of tryptophan

[edit]
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 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).[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,[12] 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.[11] 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.[10][11]

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).[10]

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.[13]

Toxicity

[edit]

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.[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

[edit]

Psychiatric disorders

[edit]

Mood disorders

[edit]

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.[15] The fact that NMDA receptor antagonists possess antidepressant 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 the cerebral spinal fluid with 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 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.[15]

Furthermore, studies have shown that unpredictable chronic mild stress (UCMS) 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.[16] There is also evidence that increased concentrations of quinolinic acid can play a role in adolescent depression.[15]

Schizophrenia

[edit]

Quinolinic acid may be involved in schizophrenia; however, there has been no research done to examine the specific effects of quinolinic acid in schizophrenia. There are many studies that show that kynurenic acid (KYNA) plays a role in the positive symptoms of schizophrenia, and there has been some research to suggest that 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]

[edit]

The cytotoxic effects of quinolinic acid elaborated upon in the toxicity section amplify cell death in neurodegenerative conditions.

Amyotrophic lateral sclerosis (ALS)

[edit]

Quinolinic acid may contribute to the causes of amyotrophic lateral sclerosis (ALS). Researchers have found elevated levels of quinolinic acid in the cerebral spinal fluid (CSF), motor cortex, and spinal cord in ALS patients. These increased concentrations of quinolinic acid could lead to neurotoxicity. In addition, quinolinic acid is associated with overstimulating NMDA receptors on motor neurons. Studies have demonstrated that quinolinic acid leads to depolarization of spinal motor neurons by interacting with the NMDA receptors on those cells in rats. Also, quinolinic acid plays a role in mitochondrial dysfunction in neurons. All of these effects could contribute to ALS symptoms.[17]

Alzheimer's disease

[edit]

Researchers have found a correlation between quinolinic acid and Alzheimer'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 with tau protein.[11][18] Furthermore, researchers have demonstrated that quinolinic acid increases tau phosphorylation in vitro in human fetal neurons [11][18] and induces ten neuronal genes including some known to correlate with Alzheimer's disease.[18] In immunoreactivity studies, researchers have found that quinolinic acid immunoreactivity is strongest in glial cells that are located close to amyloid plaques and that there is immunoreactivity with neurofibrillary tangles.[11]

Brain ischemia

[edit]

Brain ischemia is characterized by insufficient 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)

[edit]

Studies have found that there is a correlation between levels of quinolinic acid in cerebral spinal fluid (CSF) and HIV-associated neurocognitive disorder (HAND) severity. About 20% of 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 patients with 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

[edit]

In the initial stages of Huntington's disease, patients have substantially increased quinolinic acid levels, in particular in the neostriatum and cortex. 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 of microglia and increased cerebral 3-hydroxykynurenine (3-HK) levels. Furthermore, these increased levels of quinolinic acid are great enough to produce 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 striatum 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 disease phenotype.[15][19] Neurological changes produced by quinolinic acid injections include altered levels of glutamate, GABA, and other amino acids. Lesions in 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

[edit]

Quinolinic acid neurotoxicity is thought to play a role in Parkinson's disease.[17][22] Studies show that quinolinic acid is involved in the degeneration of the dopaminergic neurons in the substantia 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 in macaques. Quinolinic acid levels are too high at these sites to be controlled by KYNA, causing neurotoxicity to occur.[17]

Other

[edit]

Quinolinic acid levels are increased in the brains of children infected with a range of bacterial infections of the central nervous system (CNS),[19][21] of poliovirus patients,[21] and of Lyme disease with CNS 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, and 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

[edit]

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]

Norharmane suppresses the production of quinolinic acid, 3-hydroxykynurenine and nitric oxide synthase, thereby acting as a neuroprotectant.[24] Natural phenols such as catechin hydrate, curcumin, and epigallocatechin gallate reduce the neurotoxicity of quinolinic acid, via anti-oxidant and possibly calcium influx mechanisms.[25] 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

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References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Quinolinic acid

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Quinolinic acid, also known as pyridine-2,3-dicarboxylic acid, is an with the molecular C₇H₅NO₄ and a molecular weight of 167.12 g/mol. It features a ring substituted with groups at the 2- and 3-positions, classifying it as a pyridinecarboxylic acid. As a natural , quinolinic acid serves as a key intermediate in the of catabolism, ultimately contributing to the of (NAD⁺). In biological systems, it is present at low nanomolar concentrations in the and under normal conditions. Quinolinic acid is biosynthesized primarily through the kynurenine pathway in animals, where the essential amino acid L-tryptophan is oxidized by enzymes such as tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO), followed by subsequent steps involving kynurenine monooxygenase and 3-hydroxyanthranilic acid oxygenase (3-HAO) to yield quinolinic acid. In plants, an alternative de novo pathway derives it from L-aspartate via aspartate oxidase and quinolinate synthase. This compound is produced mainly by activated microglia and macrophages during immune responses, with elevated levels observed in inflammatory states. It occurs naturally in various foods, including cinnamon, red bell peppers, and durian, though in trace amounts. Biologically, quinolinic acid acts as an agonist of N-methyl-D-aspartate (NMDA) receptors, mimicking the excitatory glutamate and thereby influencing synaptic transmission and neuronal excitability. However, at higher concentrations, it exerts neurotoxic effects by overstimulating NMDA receptors, leading to , calcium influx, , , and mitochondrial dysfunction, which can result in neuronal or . These properties implicate quinolinic acid in the pathophysiology of various neurodegenerative and neuropsychiatric disorders, including , , , (ALS), HIV-associated neurocognitive disorders, and , where cerebrospinal fluid levels can rise up to 20-fold above baseline. Additionally, it functions as a pro-inflammatory mediator and gliotoxin, amplifying in affected tissues.

Chemical Properties and Synthesis

Structure and Properties

Quinolinic acid, systematically named , has the molecular formula C7H5NO4C_7H_5NO_4. It features a six-membered ring with groups attached at the adjacent 2- and 3-positions, conferring its character. This compound appears as a to light yellow crystalline powder with a of 188–190 °C, at which it decomposes. It exhibits moderate in (approximately 0.55 g/100 mL at ) and is slightly soluble in alcohols, but insoluble in nonpolar solvents such as and . The pKa values are 2.43 for the first dissociation and 4.78 for the second, indicating it exists predominantly as a dianion at physiological pH (around 7.4). Quinolinic acid demonstrates good stability under physiological conditions, remaining intact in biological matrices like plasma and serum for at least 24 hours at 4 °C without significant degradation. Chemically, quinolinic acid shows a tendency toward , particularly under heating or acidic conditions, where it can lose one or both carboxyl groups to form related pyridines. It also serves as a key precursor to niacin (nicotinic acid) through phosphoribosyl transfer and subsequent mediated by quinolinic acid phosphoribosyltransferase.

Synthetic Methods

One of the earliest chemical syntheses of quinolinic acid involved the preparation of methyl-substituted quinolines, such as quinaldine (2-methylquinoline), via the followed by oxidation with in alkaline medium. This approach, reported by Hoogewerff and van Dorp in 1879, targeted the conversion of the methyl group and benzene ring to yield the 2,3-dicarboxylic acid, though it suffered from very low yields and formation of significant byproducts. In the early , ozonolysis emerged as a method for oxidizing quinoline directly to quinolinic acid. Treatment of quinoline with in aqueous medium, followed by oxidative workup with , cleaves the benzene ring to produce quinolinic acid alongside cinchomeronic acid (pyridine-3,5-dicarboxylic acid), with yields of quinolinic acid reaching up to 40% under controlled conditions such as prolonged ozonization (24 hours) at . This method exploits the selective attack on the aromatic ring but requires careful handling of and separation of isomeric products. Oxidative methods using permanganate or peroxide have been refined for better efficiency. Direct oxidation of quinoline with in neutral or alkaline conditions preferentially yields quinolinic acid by degrading the moiety, though traditional protocols achieve modest yields (around 20-30%) due to over-oxidation to nicotinic acid or polycarboxylic acids. oxidation, initially developed by Stix and Bücher in 1932 using salts as catalysts in acidic medium, converts quinoline to quinolinic acid but encounters issues with low yields (less than 30%) and cumbersome purification involving precipitation of . A modern improvement employs aqueous , 30-80% (70-90% of stoichiometric amount) at 50-100°C with catalytic vanadyl, , or titanyl salts (0.01-0.1 g per mole quinoline), followed by ions to complete oxidation, achieving yields up to 52% while avoiding byproducts. Quinolinic acid is commercially available from fine chemical suppliers, primarily produced via non-biological oxidative routes from derived from or sources. However, scalability remains challenging due to moderate yields (typically below 60%), the need for multi-step purification to remove isomers and metal residues, and environmental concerns from strong oxidants like or , prompting ongoing research into greener catalytic processes. These chemical methods require excess reagents and generate , limiting large-scale industrial adoption.

Biosynthesis and Metabolism

Kynurenine Pathway Involvement

The represents the primary metabolic route for the catabolism of the in mammals, accounting for approximately 95% of its degradation and serving as a major source of (NAD+) . This pathway initiates in various tissues, particularly the liver and immune cells, where is sequentially metabolized through a series of enzymatic steps to generate intermediates that ultimately contribute to NAD+ production, a critical coenzyme in cellular energy metabolism and redox reactions. Quinolinic acid occupies a pivotal position within this pathway as a key downstream metabolite that directly feeds into NAD+ synthesis. Upstream enzymes in the , such as () and kynurenine 3-monooxygenase (KMO), play essential roles in channeling toward quinolinic acid production, with their activity markedly increased during inflammatory conditions. catalyzes the initial rate-limiting step, converting to N-formylkynurenine, which is then transformed into ; this is predominantly expressed in extrahepatic tissues like macrophages and . KMO further hydroxylates to 3-hydroxykynurenine, directing the flux toward the quinolinic acid branch and amplifying its accumulation under stress. These enzymatic actions elevate quinolinic acid levels, particularly in response to immune activation, where the pathway shifts from routine catabolism to a mechanism that modulates inflammation and cellular responses. The regulation of the kynurenine pathway, and thus quinolinic acid production, is heavily influenced by pro-inflammatory cytokines, notably interferon-gamma (IFN-γ), which induces IDO expression in immune cells such as macrophages and dendritic cells. IFN-γ, released during infections or autoimmune responses, binds to its receptor and activates signaling cascades like JAK-STAT, leading to transcriptional upregulation of IDO and subsequent enhancement of the entire pathway. This induction not only depletes local tryptophan availability but also boosts kynurenine-derived metabolites, including quinolinic acid, thereby linking immune signaling to metabolic reprogramming in inflamed tissues. While the primary route in mammals derives quinolinic acid from tryptophan via the kynurenine pathway, an alternative de novo synthesis from aspartate exists in prokaryotes and plants.

Biosynthesis Routes

Quinolinic acid is primarily synthesized in mammals through the of metabolism, where the 3-hydroxyanthranilate 3,4-dioxygenase (3-HAO) catalyzes the oxidative ring closure of 3-hydroxyanthranilic acid to form quinolinic acid. This step represents a key branch point in the pathway, leading to the de novo biosynthesis of (). The reaction requires molecular oxygen and iron as a cofactor, proceeding via a semiquinone intermediate that rearranges to yield the structure of quinolinic acid. An alternative de novo biosynthetic route for quinolinic acid exists in prokaryotes and , independent of . In this pathway, L-aspartate is first oxidized to iminoaspartate by L-aspartate oxidase (NadB), which then condenses with in a reaction catalyzed by quinolinate (NadA) to directly produce quinolinic acid. Subsequent conversion of quinolinic acid to nicotinate mononucleotide is mediated by quinolinate phosphoribosyltransferase (NadC), but the NadA step is the critical quinolinic acid-forming reaction in these organisms. In the mammalian , quinolinic acid biosynthesis via the is predominantly localized to immune-activated cells, including and infiltrating macrophages, which express high levels of 3-HAO. Pericytes in the blood-brain barrier also contribute to the by producing under inflammatory conditions, which can be further metabolized to quinolinic acid by and macrophages, though at lower rates. This cellular specificity enhances quinolinic acid levels during , linking biosynthesis to immune responses.

Metabolic Fate

Quinolinic acid, produced via the , undergoes specific metabolic processing in mammalian systems. The primary metabolic fate of quinolinic acid is its conversion to nicotinic acid mononucleotide (NAMN) by the enzyme quinolinate phosphoribosyltransferase (QPRT), a key step in the de novo biosynthesis of nicotinamide adenine dinucleotide (NAD+). This reaction utilizes 5-phospho-α-D-ribosyl-1-pyrophosphate (PRPP) as a cofactor, integrating quinolinic acid into the Preiss-Handler pathway for NAD+ production, which supports cellular energy metabolism and redox homeostasis. QPRT activity is predominantly localized in the liver and kidneys, where it efficiently salvages quinolinic acid to prevent its accumulation and potential . A significant portion of quinolinic acid that escapes enzymatic conversion is excreted primarily unchanged in the , reflecting its role as a terminal metabolite in the . Normal urinary excretion levels in healthy humans range from approximately 0 to 5.8 μg/mg , indicating efficient renal handling under baseline conditions. Renal clearance of quinolinic acid is high and comparable to glomerular rates, with studies showing it is readily dialyzable, achieving up to 94.8% reduction in plasma levels post-hemodialysis. Minor metabolites may also appear in , but unchanged quinolinic acid predominates, underscoring the kidneys' central role in its elimination. The metabolism and clearance of quinolinic acid are influenced by hepatic and renal function, as well as age-related physiological changes. Impaired liver function can reduce QPRT-mediated conversion, leading to elevated circulating levels, while kidney dysfunction decreases renal clearance, resulting in and systemic accumulation. Aging is associated with altered dynamics, including increased brain quinolinic acid levels and a tendency for decreased hepatic and renal processing efficiency, which may contribute to reduced clearance rates in older individuals. These factors highlight the interplay between organ function and age in modulating quinolinic acid's metabolic disposition.

Biological Roles

In Immune Response

Quinolinic acid is upregulated during infections and autoimmune responses through the activation of (IDO) in antigen-presenting cells such as dendritic cells and macrophages. This enzyme, induced by proinflammatory cytokines like interferon-gamma, initiates the , leading to increased production of quinolinic acid as a downstream metabolite. In response to immune stimulation, such as during viral infections or chronic inflammation, IDO expression surges, elevating quinolinic acid levels systemically and locally in affected tissues. In immune-mediated tissue damage, quinolinic acid contributes to cytotoxicity against non-neuronal cells, notably in autoimmune conditions like where it targets . Activated and macrophages in the produce quinolinic acid via the , inducing death through excitotoxic and oxidative mechanisms. This process exacerbates demyelination and tissue injury during inflammatory flares, as observed in experimental autoimmune encephalomyelitis models of . Recent research highlights quinolinic acid's role in linking to remote organ effects, particularly in via the . In patients with declining kidney function, upregulated activity in renal and immune cells elevates circulating quinolinic acid, which crosses the blood-brain barrier and induces neuroinflammatory responses. Studies from 2025 demonstrate that this metabolite bridges kidney injury to cognitive and neuronal impairments by amplifying and immune activation in the brain.

As NMDA Agonist

Quinolinic acid serves as a potent endogenous at N-methyl-D-aspartate (NMDA) receptors, binding directly to these ionotropic glutamate receptors and eliciting excitatory responses comparable to those of glutamate and aspartate. This activation promotes calcium influx through receptor-associated channels, initiating intracellular signaling cascades essential for neuronal communication. Unlike glutamate, quinolinic acid is not subject to rapid by neuronal or glial transporters, which extends its duration of action at the synaptic cleft. The agonist activity of quinolinic acid demonstrates selectivity for subtypes incorporating the NR2A and NR2B subunits, distinguishing it from broader interactions and enabling targeted modulation of receptor function. Under normal physiological conditions, this selective binding supports by enhancing neuronal excitability and facilitating mechanisms such as , thereby contributing to learning and memory processes in regions like the and hippocampus. Quinolinic acid thus plays a role in balancing excitatory with safeguards against overactivation. Endogenous concentrations of quinolinic acid remain low in the healthy , typically around 1-2 nmol/g wet in various regions such as the cortex and hippocampus of models, reflecting tightly regulated production via the . These levels are dynamically modulated by kynurenic acid, a fellow pathway metabolite that acts as a competitive , thereby dampening quinolinic acid's excitatory influence and preserving synaptic . Quinolinic acid production can increase modestly during immune activation to fine-tune this neuromodulatory balance.

Toxicity Mechanisms

Neurotoxic Effects

Quinolinic acid administration in animal models consistently induces , neuronal death, and lesions, mimicking excitotoxic damage observed with other neurotoxins. Intracerebral injections into the hippocampus, for example, trigger acute activity followed by selective degeneration of pyramidal neurons in the CA1 and CA3 regions, with CA2 cells showing greater resistance. This toxicity arises from quinolinic acid's activation of NMDA receptors. Similar intrahippocampal doses of 40–120 nmol produce dose-related neuronal loss, ranging from minimal damage at lower levels to extensive at higher concentrations. Particular neural regions demonstrate heightened vulnerability to quinolinic acid's effects. The is highly susceptible, where unilateral injections lead to axon-sparing lesions characterized by marked dendritic swelling, disruption of cellular architecture, and preferential loss of medium spiny neurons. The and motor neurons also exhibit sensitivity, with intracortical or applications resulting in localized neuronal degeneration and functional impairments in . These regional patterns underscore quinolinic acid's selective impact on pathways in . The neurotoxic outcomes are profoundly dose-dependent, as evidenced by intrastriatal infusions in rats that cause progressive neurodegeneration: 6 nmol/h leads to approximately 70% neuronal loss, escalating to 90% at 10 nmol/h over one week. Systemic LD50 values in exceed 500 mg/kg orally, indicating low acute lethality via this route but highlighting the compound's potency through direct neural exposure. In humans, elevated cerebrospinal fluid quinolinic acid concentrations—often reaching micromolar levels—correlate with adverse neurological outcomes, including increased mortality after and progressive brain atrophy in HIV-associated neurocognitive disorders.

Cellular and Molecular Pathways

Quinolinic acid exerts its toxicity primarily through overactivation of N-methyl-D-aspartate (NMDA) receptors, acting as an that binds to these sites and triggers excessive influx of calcium ions into cells. This sustained receptor stimulation leads to , where elevated intracellular calcium disrupts mitochondrial function by opening the permeability transition pore, impairing ATP production, and releasing pro-apoptotic factors that culminate in . Secondary consequences of this calcium overload include the generation of (ROS), which drive and , damaging cellular membranes and amplifying neurotoxic cascades. Additionally, ROS-mediated oxidation contributes to cytoskeletal disruption, such as microtubule depolymerization through modification of residues, thereby impairing neuronal structure and transport mechanisms. Quinolinic acid's toxicity further intersects with DNA repair pathways, where calcium-induced ROS cause DNA strand breaks that hyperactivate poly(ADP-ribose) polymerase (PARP), leading to rapid depletion of nicotinamide adenine dinucleotide (NAD+) and energetic collapse.

Clinical Implications

Psychiatric Disorders

Quinolinic acid, a neurotoxic metabolite of the kynurenine pathway, has been implicated in the pathophysiology of major depressive disorder (MDD) through elevated levels in cerebrospinal fluid (CSF), which correlate with the severity of depressive symptoms. Studies have shown that CSF quinolinic acid concentrations are increased in patients with MDD, particularly in contexts of inflammation-induced depression such as during interferon-alpha therapy, where higher levels align with greater symptom intensity on scales like the Hamilton Depression Rating Scale. This elevation is thought to contribute to excitotoxic effects via overstimulation of N-methyl-D-aspartate (NMDA) receptors, exacerbating mood dysregulation. In (BD), similarly elevated CSF quinolinic acid levels have been observed, often during depressive episodes, with an increased quinolinic acid-to-picolinic acid ratio persisting in patients with and sustained over follow-up periods of up to two years. These findings suggest that quinolinic acid dysregulation may underlie the chronic neuroinflammatory state in BD, impairing glial-neuronal interactions and contributing to mood instability. A higher quinolinic acid-to-kynurenic acid ratio in mood disorders further supports this link, as meta-analyses indicate potential increases in quinolinic acid, though sample sizes limit definitive conclusions. Regarding , increased activity of the in the brain, particularly in the , has been associated with excitotoxic damage mediated by quinolinic acid. Post-mortem analyses reveal alterations in enzymes, such as reduced kynurenine 3-monooxygenase and 3-hydroxyanthranilic acid dioxygenase activity in prefrontal regions, which decrease metabolism toward neurotoxic branches, potentially contributing to prefrontal cortical dysfunction through altered NMDA receptor-mediated signaling and increased kynurenic acid. Evidence from preclinical models demonstrates that inhibiting (IDO), a key enzyme activating the , reduces depressive-like behaviors, providing insight into quinolinic acid's role across psychiatric conditions. In lipopolysaccharide-induced models, IDO inhibition with compounds like 1-methyltryptophan attenuates microglial activation in the and hippocampus, blocking immobility in forced swim tests indicative of despair. Similarly, in chronic pain-depression comorbidity models, IDO1 knockout or inhibition prevents the development of and behavioral despair by limiting flux toward quinolinic acid. These findings highlight IDO as a potential target for mitigating quinolinic acid-driven psychiatric symptoms.

Neurodegenerative Diseases

Quinolinic acid (QUIN), a neurotoxic of the , contributes to progressive neuronal loss in several neurodegenerative diseases by inducing through overactivation of N-methyl-D-aspartate (NMDA) receptors, leading to calcium influx, , and cell death. In these conditions, immune activation in the elevates QUIN production, particularly from activated and macrophages, amplifying inflammatory cascades that exacerbate neurodegeneration. This section examines QUIN's specific roles in (ALS), (AD), (HD), (PD), and . In , microglial activation drives QUIN synthesis via the , promoting excitotoxic damage to s and accelerating disease progression. Studies have demonstrated that QUIN is predominantly produced by activated in the and , where it sensitizes NMDA receptors on vulnerable neurons, contributing to their selective degeneration. (CSF) levels of QUIN are significantly elevated in ALS patients compared to healthy controls, correlating with disease severity and motor neuron loss. For instance, QUIN concentrations in CSF from ALS individuals were found to be markedly higher, reflecting ongoing and supporting its role as a of microglial involvement in . In , QUIN correlates with amyloid-beta (Aβ) plaques and pathology, particularly in the hippocampus, where it mediates that disrupts synaptic function and promotes neuronal . Elevated QUIN levels enhance hyperphosphorylation at sites associated with paired helical filaments, a hallmark of neurofibrillary tangles, through NMDA receptor-dependent signaling pathways. Hippocampal immunoreactivity for QUIN and its synthetic enzymes, such as , is increased in AD brains, linking dysregulation to Aβ-induced inflammation and cognitive decline. This excitotoxic mechanism amplifies hippocampal vulnerability, contributing to memory impairment in early AD stages. In and , QUIN exacerbates striatal and neuron vulnerability, respectively. In HD, QUIN's neurotoxic effects target medium spiny neurons in the , promoting oxidative damage and chorea-like symptoms through unbalanced metabolism favoring the neurotoxic branch. However, meta-analyses as of 2024 do not support consistent CSF QUIN elevations in HD. For PD, QUIN contributes to cell loss in the by inducing mitochondrial dysfunction and , with some studies reporting higher CSF QUIN levels associated with symptom severity. As of 2025, meta-analyses confirm alterations in AD with variable QUIN levels across neurodegenerative diseases, highlighting ongoing research into therapeutic targeting. In , acute surges in QUIN following amplify infarct size by intensifying excitotoxic injury in the ischemic penumbra. Post-ischemic activation of the leads to rapid QUIN accumulation in tissue, correlating with larger volumes and worse neurological outcomes. Preclinical models show that QUIN peaks within hours of reperfusion, enhancing NMDA-mediated calcium overload and secondary that expands the infarct core. A 2019 systematic review of involvement in confirmed these acute elevations in tissue.

Systemic and Infectious Conditions

In , elevated levels of quinolinic acid in the contribute to the development of , primarily through the activation of macrophages and that produce this as part of the . Macrophages stimulated by or interferon-gamma increase quinolinic acid production, exacerbating excitotoxic damage in the . This elevation correlates with the severity of and observed in advanced disease stages. In , an autoimmune demyelinating disorder, quinolinic acid exerts toxicity on , the cells responsible for production, thereby contributing to demyelination and formation. Studies demonstrate that quinolinic acid, alongside inflammatory cytokines like TNF-alpha, induces in oligodendroglial cells , mimicking the inflammatory environment of the disease. Elevated quinolinic acid levels in the of patients reflect dysregulated activity, which amplifies neurotoxic effects during active inflammation. Recent research from 2025 highlights the , including quinolinic acid accumulation, as a mechanistic link between , , and secondary brain toxicity. In patients with declining kidney function, upregulated metabolism leads to increased circulating quinolinic acid, which crosses the blood-brain barrier and promotes , potentially worsening cognitive outcomes in comorbid neurological conditions. Beyond these, quinolinic acid shows implications in , where peripheral elevations from activated immune cells drive through neurotoxic metabolites. In autoimmune disorders such as systemic lupus erythematosus and autoimmune , peripheral increases in quinolinic acid correlate with disease activity and inflammation, suggesting a role in systemic immune dysregulation.

Therapeutic Strategies

Pathway Modulation

Pathway modulation strategies aim to reduce quinolinic acid production by targeting key enzymes in the , thereby mitigating its neurotoxic effects from overactivation. (IDO) serves as the rate-limiting enzyme upstream in catabolism, converting to and promoting downstream quinolinic acid synthesis. Inhibitors such as 1-methyl block IDO activity, reducing levels and subsequently lowering quinolinic acid accumulation in preclinical models of inflammation-driven neurodegeneration. Direct inhibition of 3-hydroxyanthranilate 3,4-dioxygenase (3-HAO), the enzyme immediately preceding quinolinic acid formation, offers a targeted approach to prevent its biosynthesis from 3-hydroxyanthranilic acid. Compounds like NCR-631, a 3-HAO inhibitor, have demonstrated reduced quinolinic acid production and neuroprotection in animal studies of excitotoxic damage. Clinical trials exploring kynurenine pathway modulators for depression and neurodegeneration remain limited as of 2025, with most direct IDO and 3-HAO inhibitors in preclinical or early-phase stages due to challenges in specificity and bioavailability. As of November 2025, clinical translation remains preclinical-dominant, with recent 2025 studies demonstrating IDO1 inhibition's benefits in PD mouse models via gut microbiota modulation and neurogenesis. Indirect modulation via minocycline, which suppresses IDO induction by inhibiting proinflammatory cytokines, has been evaluated in randomized, placebo-controlled trials for major depressive disorder; a 2023 meta-analysis of RCTs showed significant improvement in depressive symptoms (SMD -0.68 on Hamilton Depression Rating Scale) and superior response rates over placebo (RR 2.51). IDO inhibitors like epacadostat, developed for cancer, show preclinical potential for neuroinflammatory conditions including Alzheimer's via kynurenine pathway modulation, but no human trials in neurodegeneration have been reported as of 2025. Preclinical studies as of 2025, such as IDO1 inhibition in mouse models, show potential benefits in Parkinson's by reducing neuroinflammation and quinolinic acid, but human clinical trials remain lacking.

Neuroprotection Approaches

One key strategy to counteract quinolinic acid's neurotoxic effects involves the use of antagonists, which block excessive glutamate-mediated at the receptor level. , a non-competitive NMDA antagonist, has demonstrated protection against quinolinic acid-induced hippocampal neuronal damage in rodent models by preventing calcium influx and subsequent cell death. Similarly, kynurenic acid and its synthetic analogs act as competitive antagonists at the glycine site of NMDA receptors, reducing quinolinic acid-evoked in striatal and cortical neurons; for instance, analogs like 7-chloro-kynurenic acid exhibit enhanced blood-brain barrier penetration and neuroprotective efficacy in ischemia and models without impairing cognitive function. Antioxidant compounds target quinolinic acid-induced and , preserving cellular integrity downstream of receptor activation. Alpha-lipoic acid mitigates quinolinic acid in human cells by lowering (ROS) levels, restoring mitochondrial function, and preventing arrest, with significant protection observed at concentrations of 100-500 μM. , a polyphenolic , attenuates quinolinic acid-induced in by upregulating Nrf2 activity, reducing protein carbonyl content as a marker of oxidative damage, and preserving (BDNF) levels, thereby improving motor deficits in models. Polyphenols like attenuate quinolinic acid-induced in striatal slices by scavenging free radicals and inhibiting , as shown in preclinical studies. Emerging therapies focus on cellular repair and pathway modulation to provide long-term against quinolinic acid. transplantation has shown promise in quinolinic acid-lesioned rat models of , where intrastriatal administration reduces behavioral impairments, striatal atrophy, and neuronal loss over 6 weeks by secreting and modulating inflammation. approaches, such as (AAV)-mediated overexpression of kynurenine aminotransferases to boost endogenous kynurenic acid production, are being explored in preclinical models to shift the toward neuroprotection and limit quinolinic acid accumulation, though clinical translation remains in early stages.

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