The percentage of viable cells in N18D3 cells decreases with quinolinic acid (0-50 mM; 24 hours), ranging from 100±0.01% at 5 mM to 45.23±0.01% at 50 mM [2].

Cell viability assay [2]
Cell Types: N18D3 cells, a hybrid neural cell line obtained from the fusion of 4-week-old Balb/C mouse dorsal root ganglion and mouse neuroblastoma N18TG2 cells
Tested Concentrations: 0, 10, 20, 30 , 40, 50 mM
Incubation Duration: 24 hrs (hours)
Experimental Results: The percentage of viable cells diminished accordingly, ranging from 100±0.01% at 5 mM to 45.23±0.01% at 50 mM.

Metabolism / Metabolites
Kynuronine is a metabolite of tryptophan in the kynuronine pathway, located at a branch point of this pathway, where it synthesizes quinolinic acid and kynuric acid. Kynuric acid is an antagonist of glutamate receptors; however, quinolinic acid is a selective agonist of NMDA receptors and has been shown to have excitotoxic effects. A high quinolinic acid/kynuric acid ratio is associated with various neurological disorders involving excitotoxic neuronal death, such as AIDS-related dementia and stroke. Inhibition of key enzymes in this pathway (kynuronidase and kynuronine 3-hydroxylase) reduces the quinolinic acid/kynuric acid ratio, which may have neuroprotective effects. This study investigated the incorporation of tritium-labeled quinolinic acid, kynuric acid, and other kynuronine pathway metabolites into the striatum of normal rats and quinolinic acid-injured rats via local in vivo injection of [5-3H]kynuronine. The time course of metabolite accumulation was assessed from 15 minutes to 4 hours after injection of [5-3H]kynurenine. Rats were sacrificed 2 hours after injection of 1.5–1500 μM [5-3H]kynurenine to investigate the concentration-dependent metabolism of kynurenine. Labeled quinolinic acid, kynurenic acid, 3-hydroxykynurenine (3-HK), 3-hydroxy-2-aminobenzoic acid, and xanthuric acid were recovered from the striatum in each experiment. An increased injury-induced kynurenine metabolism was observed after injection of 15 μM [5-3H]kynurenine. Consequently, the recoveries of [3H]kynurenic acid (5.0% vs. 1.8%), [3H]3-HK (20.9% vs. 4.5%), [3H]xanthuric acid (1.5% vs. 0.4%), and [3H]quinolinic acid (3.6% vs. 0.6%) were significantly increased in the injured striatum. Increased kynurenine metabolism in damaged tissue was evident at all time points and at all kynurenine concentrations. The increased activities of damage-induced kynurenine-3-hydroxylase (3.6-fold), kynurenase (7.6-fold), kynurenine aminotransferase (1.8-fold), and 3-hydroxy-2-aminobenzoic acid oxygenase (4.2-fold) likely contributed to the enhanced flux of this pathway in the damaged striatum. These data provide evidence for the existence of a functional kynurenine metabolic pathway in the normal rat brain and indicate a significant increase in flux after neuronal ablation. Kynurenine is an intermediate in the tryptophan-to-nicotinic acid pathway. Kynurenine is generated in the mammalian brain (40%) and absorbed from peripheral tissues (60%), indicating its ability to cross the blood-brain barrier. In the brain, kynurenine can be converted into two other components of this pathway: the neurotoxic quinolinic acid and the neuroprotective kynurenic acid. Quinolinic acid is perhaps the most extensively studied kynurenine metabolite because it may lead to excitotoxic neuronal loss and seizures through its interaction with the N-methyl-D-aspartate receptor complex (a glutamate receptor). Kynurenic acid is another metabolite of kynurenine; its synthesis is catalyzed by kynurenine aminotransferase. It is currently the only known endogenous N-methyl-D-aspartate receptor inhibitor that acts on the glycine site on the receptor complex. Furthermore, kynurenic acid noncompetitively inhibits α7 nicotinic acetylcholine presynaptic receptors (nAChRs), thereby inhibiting glutamate release and regulating α4β2 nAChR expression. Activation of excitatory amino acid receptors is well-known to play a role in various neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, stroke, and epilepsy. Numerous studies have explored whether the excitatory amino acid receptor antagonist kynurenic acid could have therapeutic effects on these neurological diseases. It has been confirmed that kynurenic acid's ability to cross the blood-brain barrier is very limited. The kynurenine pathway is a major pathway for tryptophan metabolism. L-Kynurine is a core compound in this pathway because it can be converted into either kynuric acid, which has neuroprotective effects, or quinolinic acid, which has neurotoxic effects. Disruptions in the balance of these endogenous compounds are observed in many diseases. This is seen in neurodegenerative diseases such as Parkinson's disease, Huntington's disease, and Alzheimer's disease; it is also seen in stroke, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, and mental disorders such as schizophrenia and depression. Elevated quinolinic acid concentrations or decreased kynuric acid concentrations may exacerbate symptoms in a variety of diseases. Numerous studies have shown that kynuric acid levels are reduced in patients with Parkinson's disease. Notably, in animal studies, kynuric acid treatment can prevent quinolinic acid-induced striatal damage in mice. For more complete data on the metabolism/metabolites of quinolinic acids (6 in total), please visit the HSDB record page.

Interactions
This study investigated the effects of S-allyl cysteine, a garlic-derived free radical scavenger with well-defined properties, on quinolinic acid-induced striatal neurotoxicity and oxidative damage. To this end, S-allyl cysteine (150, 300, or 450 mg/kg) was administered intraperitoneally 30 minutes before a single perfusion of 1 μL quinolinic acid (240 nmol) into the striatum of rats. Low doses (150 mg/kg) of S-allyl cysteine effectively inhibited only quinolinic acid-induced lipid peroxidation (P < 0.05), while systemic injection of 300 mg/kg of the compound effectively reduced quinolinic acid-induced oxidative damage, manifested as striatal reactive oxygen species generation (P < 0.01) and lipid peroxidation (P < 0.05). S-allyl cysteine (300 mg/kg) also prevented the quinolinic acid-induced decrease in striatal copper/zinc superoxide dismutase activity (P < 0.05). Furthermore, at the same dose, S-allyl cysteine alleviated quinolinic acid-induced neurotoxicity, manifested as circling behavior (P < 0.01) and striatal morphological changes. In summary, S-allyl cysteine alleviates quinolinic acid-induced striatal toxicity in vivo through the following mechanisms: (a) free radical scavenging; (b) reducing oxidative stress; and (c) maintaining the activity of striatal copper/zinc superoxide dismutase (Cu,Zn-SOD). This antioxidant effect appears to be the reason for maintaining the morphological and functional integrity of the striatum. …Oxidative damage to biomolecules was tracked by measuring lipid peroxidation and protein carbonylation levels in rat brain tissue cultures after 24 hours of treatment with 0.5 mM quinolinic acid. Quinolinic acid enhanced lipid peroxidation in the early stages of tissue culture and enhanced protein carbonylation in the later stages. Melatonin is a multifunctional antioxidant and neuroprotective agent, acting as both a free radical scavenger and a signaling molecule. It completely inhibits the pro-oxidative effects of quinolinic acid at a concentration of 1 mM. The morphological damage and neurotoxicity induced by quinolinic acid were assessed using optical microscopy. Quinolinic acid caused widespread apoptosis/necrosis, while melatonin significantly alleviated this damage. Combined treatment with melatonin produced a significant protective effect, antagonizing the neurotoxicity induced by quinolinic acid. Quinolinic acid increased the activity of glutathione reductase and catalase, while melatonin antagonized these effects. Furthermore, melatonin induced superoxide dismutase activity. Quinolinic acid and melatonin independently regulate the activity of antioxidant enzymes through different mechanisms. This study investigated the neuroprotective effect of melatonin on quinolinic acid-induced hippocampal neuronal degeneration in rats. Rats were divided into three groups and received intra-hippocampal injections before or after quinolinic acid injection: saline, quinolinic acid, or intraperitoneal melatonin. Five days after injection, brain tissue was removed, and hippocampal sections were stained for microscopic examination or for glutamate receptor binding studies. Results showed that melatonin could protect hippocampal neurons from quinolinic acid-induced neurodegeneration and partially prevent the reduction in the number of glutamate receptors caused by quinolinic acid. Therefore, melatonin has the potential to alleviate hippocampal neuronal damage caused by neurotoxins such as quinolinic acid. PMID: 9704893
To investigate the effect of the caspase-1 inhibitor Ac-YVAD-CHO on quinolinic acid (QA)-induced apoptosis… Before injecting QA (60 nmol) into the striatum, rats were pretreated with Ac-YVAD-CHO (2–8 μg) in the striatum. Total striatal protein, genomic DNA, and nucleoproteins were isolated. This study used enzyme activity assays, agarose gel electrophoresis, electrophoretic mobility shift analysis, and Western blotting to investigate the effects of Ac-YVAD-CHO on QA-induced caspase-1 activity, internuclear DNA fragmentation, IκB-α degradation, NF-κB and AP-1 activation, and p53 protein elevation. …Ac-YVAD-CHO pretreatment inhibited QA-induced internuclear DNA fragmentation. Ac-YVAD-CHO inhibited QA-induced caspase-1 activity and p53 protein elevation, but had no effect on QA-induced IκB-α degradation, NF-κB, or AP-1 activation. The authors concluded that caspase-1 is involved in QA-induced p53 upregulation but not in IκB-α degradation. Inhibition of caspase-1 attenuated QA-induced rat striatal cell apoptosis.
For more complete data on interactions of quinolinates (31 in total), please visit the HSDB record page.

[1]. Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. Brain. 1992 Oct;115 ( Pt 5):1249-73.

[2]. Neuroprotective effects of (-)-epigallocatechin-3-gallate against quinolinic acid-induced excitotoxicity via PI3K pathway and NO inhibition. Brain Res. 2010 Feb 8;1313:25-33.

Quinolinic acid is a pyridine dicarboxylic acid with carboxyl groups substituted at positions 2 and 3 of its pyridine ring. It is a metabolite of tryptophan. Quinolinic acid acts as an NMDA receptor agonist and is found in humans, mice, and E. coli. It is the conjugate acid of quinolinic acid (1-) and quinolinic acid. Quinolinic acid is present in or produced by E. coli (K12 strain, MG1655 strain). Quinolinic acid has also been reported in humans, Mangosteen, and other organisms with relevant data. Quinolinic acid is an intermediate product of the kynurenine pathway, which is responsible for converting the amino acid tryptophan into the potentially neurotoxic nicotinamide adenine dinucleotide. Excessive production of quinolinic acid can cross the blood-brain barrier (BBB) and act as an N-methyl-D-aspartate (NMDA) receptor agonist, potentially leading to neuronal damage and neurodegenerative brain diseases. The NMDA receptor is a heterotetramer, ligand-gated, voltage-dependent glutamate receptor crucial for synaptic plasticity, learning, and memory. Quinolinic acid is a metabolite found or produced in Saccharomyces cerevisiae. It is a metabolite of tryptophan and may play a role in neurodegenerative diseases. Elevated quinolinic acid levels in cerebrospinal fluid are associated with the severity of neuropsychiatric deficits in HIV patients. Mechanism of Action Huntington's disease is an autosomal dominant inherited neurological disorder characterized by progressive chorea, cognitive impairment, and mood disorders. It typically occurs in middle age, and symptoms inevitably progress to mental and physical dysfunction. Some studies have speculated that excitoxins are involved in the pathogenesis of Huntington's disease. Research by Schwarcz and colleagues shows that quinolinic acid can produce axon-preserving lesions similar to those observed in Huntington's disease. These lesions lead to the depletion of neurotransmitters (such as γ-aminobutyric acid (GABA)) in striatal spinous neurons, while dopamine remains unaffected. Recently, some researchers have found a paradoxical 3-5 fold increase in somatostatin and neuropeptide Y levels in the striatum of Huntington's disease patients, attributed to the selective retention of a subclass of striatal nonspinous neurons, where these peptides are co-localized. In this study, the authors demonstrated that quinolinic acid-induced damage is very similar to that in Huntington's disease, both leading to a significant reduction in GABA and substance P, while somatostatin/neuropeptide Y neurons are selectively unaffected. Damage induced by karyophylline (KA), isopentenyl acid (IA), and N-methyl-D-aspartate (MeAsp) differs from that quinolinic acid-induced damage; they affect all cell types and do not affect somatostatin/neuropeptide Y neurons. These results suggest that quinolinic acid or similar compounds may be the cause of neuronal degeneration in Huntington's disease. To determine whether caspase cleavage of huntingtin protein is a key event in neuronal dysfunction and selective neurodegeneration in Huntington's disease, the authors constructed YAC mice expressing caspase-3 and caspase-6 resistant mutant huntingtin protein. Mice expressing mutant huntingtin protein were resistant to caspase-6 cleavage but insensitive to caspase-3 cleavage, maintaining normal neuronal function and avoiding striatal neurodegeneration. Furthermore, these caspase-6 resistant mutant huntingtin protein mice were also resistant to neurotoxicity induced by various stressors, including NMDA, quinolinic acid, and astrocytocin. These results are consistent with the understanding that the proteolysis of huntingtin protein at the caspase-6 cleavage site is an important event mediating neuronal dysfunction and neurodegeneration, highlighting the important role of huntingtin protein hydrolysis and excitotoxicity in Huntington's disease. ...Excitotoxic injury to the rat brain using the N-methyl-D-aspartate receptor agonist quinolinic acid induced the expression of p53 mRNA and protein in brain regions exhibiting delayed DNA fragmentation, with p53 mRNA expression preceding DNA damage detected by dUTP-biotin nick-end labeling mediated by terminal deoxynucleotidyl transferase. Furthermore, in situ hybridization and immunocytochemistry demonstrated increased expression of the p53-responsive gene Gadd-45 (preceding p53 expression) and re-expression of the p53-responsive gene Bax (following p53 expression) in these same brain regions. Studies have shown that Bax promotes neuronal death through interaction with Bcl-2 family members, while Gadd-45 expression is associated with cell cycle inhibition and DNA repair. These results suggest that p53 protein may act as an active transcription factor in damaged brain tissue, potentially initiating the re-expression of Bax in damaged brain regions. However, since Gadd-45 expression precedes p53 expression, p53 is unlikely to be involved in regulating the early expression of Gadd-45. In summary, these results suggest that p53, Bax, and Gadd-45 may play important roles in the brain tissue response (damage/recovery) following excitotoxic injury. The kynurenine pathway is a major pathway in L-tryptophan catabolism, producing a variety of bioactive molecules. Among these, the neurotoxin quinolinic acid is considered to be involved in the pathogenesis of various inflammatory neurological diseases. Most current explanations of Alzheimer's disease pathogenesis focus on the accumulation of amyloid-β peptide (Aβ), which forms senile plaques as insoluble deposits and neurofibrillary tangles composed of hyperphosphorylated Tau protein. Aβ accumulation is considered an early and crucial step in the neuropathogenesis of Alzheimer's disease. Existing evidence suggests that the kynurenine pathway is associated with Alzheimer's disease. Disorders of the kynurenine pathway have been found in Alzheimer's disease. Recently, the authors demonstrated that the cleavage product of amyloid precursor protein, Aβ1-42, can induce macrophages (especially microglia) to produce neurotoxic concentrations of quinolinic acid. Evidence suggests that senile plaques in Alzheimer's disease are associated with chronic local inflammation, particularly activated microglia. A major aspect of quinolinic acid toxicity is lipid peroxidation, and biomarkers of lipid peroxidation have also been found in Alzheimer's disease. These data collectively suggest that quinolinic acid may be a key factor in the pathogenesis of neuronal damage in Alzheimer's disease. This review describes multiple associations between the kynurenine pathway and the neuropathogenesis of Alzheimer's disease, highlighting the neurotoxicity of quinolinic acid and emphasizing its role in lipid peroxidation and amplification of local inflammation. More complete data on the mechanisms of action of quinolinic acid (15 in total) can be found on the HSDB record page.

C7H5NO4

167.1189

167.021

89-00-9

Quinolinic acid-d3;138946-42-6;Quinolinic acid-13C7;1346642-91-8;Quinolinic acid-13C4,15N

1066

White to off-white solid powder

1.6±0.1 g/cm3

425.0±30.0 °C at 760 mmHg

188-190ºC

210.9±24.6 °C

0.0±1.1 mmHg at 25°C

1.628

-1.44

2

5

2

12

204

0

GJAWHXHKYYXBSV-UHFFFAOYSA-N

InChI=1S/C7H5NO4/c9-6(10)4-2-1-3-8-5(4)7(11)12/h1-3H,(H,9,10)(H,11,12)

pyridine-2,3-dicarboxylic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~33.33 mg/mL (~199.44 mM)
H2O : ~3.33 mg/mL (~19.93 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (14.96 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (14.96 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (14.96 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 9.09 mg/mL (54.39 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)