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
Kynurenine, a metabolite of tryptophan along the 'kynurenine pathway', is at a branch point of the pathway which can lead to the synthesis of both quinolinic acid and kynurenic acid. kynurenic acid is an antagonist of glutamate receptors; however, quinolinic acid is a selective agonist of NMDA receptors, and has been shown to act as an excitotoxic agent. A high quinolinic acid/kynurenic acid ratio has been implicated in a variety of neurological diseases in which excitotoxic neuronal cell death is found, e.g. AIDS-related dementia, stroke, etc. Inhibiting the key enzymes of this pathway (i.e. kynureninase and kynurenine 3-hydroxylase) would lower the quinolinic acid/kynurenic acid ratio, which may potentially have neuroprotective effects.
The incorporation of tritium-label into quinolinic acid, kynurenic acid, and other kynurenine pathway metabolites was studied in normal and quinolinic acid-lesioned rat striata after a focal injection of [5-3H]kynurenine in vivo. The time course of metabolite accumulation was examined 15 min to 4 hr after injection of [5-3H]kynurenine, and the concentration dependence of kynurenine metabolism was studied in rats killed 2 hr after injection of 1.5-1,500 uM [5-3H]kynurenine. Labeled quinolinic acid, kynurenic acid, 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid, and xanthurenic acid were recovered from the striatum in every experiment. Following injection of 15 uM [5-3H]kynurenine, a lesion-induced increase in kynurenine metabolism was noted. Thus, the proportional recoveries of [3H]kynurenic acid (5.0 vs. 1.8%), [3H]3-HK (20.9 vs. 4.5%), [3H]xanthurenic acid (1.5 vs. 0.4%), and [3H]quinolinic acid (3.6 vs. 0.6%) were markedly elevated in the lesioned striatum. Increases in kynurenine metabolism in lesioned tissue were evident at all time points and kynurenine concentrations used. Lesion-induced increases of the activities of kynurenine-3-hydroxylase (3.6-fold), kynureninase (7.6-fold), kynurenine aminotransferase (1.8-fold), and 3-hydroxyanthranilic acid oxygenase (4.2-fold) likely contributed to the enhanced flux through the pathway in the lesioned striatum. These data provide evidence for the existence of a functional kynurenine pathway in the normal rat brain and for a substantial increase in flux after neuronal ablation.
Kynurenine is an intermediate in the pathway of the metabolism of tryptophan to nicotinic acid. Kynurenine is formed in the mammalian brain (40%) and is taken up from the periphery (60%), indicating that it can be transported across the blood-brain barrier. In the brain, kynurenine can be converted to two other components of the pathway: the neurotoxic quinolinic acid and the neuroprotective kynurenic acid. Quinolinic acid is probably the most widely studied metabolite of kynurenine, because it may cause excitotoxic neuronal cell loss and convulsions by interacting with the N-methyl-D-aspartate receptor complex, a type of glutamate receptor. Kynurenic acid is another metabolite of kynurenine; its synthesis is catalysed by kynurenine aminotransferases. This is the only known endogenous N-methyl-D-aspartate receptor inhibitor, which can act at the glycine site on the receptor complex. Furthermore, kynurenic acid non-competitively inhibits alpha7 nicotinic acetylcholine presynaptic receptors (nAChRs), inhibiting glutamate release, and regulates the expression of alpha4beta2 nAChR. It is well-known that the activation of excitatory amino acid receptors can play a role in a number of neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, stroke and epilepsy. Various studies have been made of whether the excitatory amino acid receptor antagonist kynurenic acid can exert a therapeutic effect in these neurological disorders. It has been established that kynurenic acid has only a very limited ability to cross the blood-brain barrier.
The kynurenine pathway is the main pathway of tryptophan metabolism. L-kynurenine is a central compound of this pathway since it can change to the neuroprotective agent kynurenic acid or to the neurotoxic agent quinolinic acid. The break-up of these endogenous compounds' balance can be observable in many disorders. It can occur in neurodegenerative disorders, such as Parkinson's disease, Huntington's and Alzheimer's disease, in stroke, in epilepsy, in multiple sclerosis, in amyotrophic lateral sclerosis, and in mental failures, such as schizophrenia and depression. The increase of quinolinic acid concentration or decrease of kynurenic acid concentration could enhance the symptoms of several diseases. According to numerous studies, lowered kynurenic acid level was found in patients with Parkinson's disease. It can be also noticeable that kynurenic acid-treatment prevents against the quinolinic acid-induced lesion of rat striatum in animal experiments.
For more Metabolism/Metabolites (Complete) data for QUINOLINIC ACID (6 total), please visit the HSDB record page.

Interactions
...This work ... investigated the effect of a garlic-derived compound and well-characterized free radical scavenger, S-allylcysteine, on quinolinic acid-induced striatal neurotoxicity and oxidative damage. For this purpose, rats were administered S-allylcysteine (150, 300 or 450 mg/kg, i.p.) 30 min before a single striatal infusion of 1 uL of quinolinic acid (240 nmol). The lower dose (150 mg/kg) of S-allylcysteine resulted effective to prevent only the quinolinate-induced lipid peroxidation (P < 0.05), whereas the systemic administration of 300 mg/kg of this compound to rats decreased effectively the quinolinic acid-induced oxidative injury measured as striatal reactive oxygen species formation (P < 0.01) and lipid peroxidation (P < 0.05). S-Allylcysteine (300 mg/kg) also prevented the striatal decrease of copper/zinc-superoxide dismutase activity (P < 0.05) produced by quinolinate. In addition, S-allylcysteine, at the same dose tested, was able to reduce the quinolinic acid-induced neurotoxicity evaluated as circling behavior (P < 0.01) and striatal morphologic alterations. In summary, S-allylcysteine ameliorates the in vivo quinolinate striatal toxicity by a mechanism related to its ability to: (a) scavenge free radicals; (b) decrease oxidative stress; and (c) preserve the striatal activity of Cu,Zn-superoxide dismutase (Cu,Zn-SOD). This antioxidant effect seems to be responsible for the preservation of the morphological and functional integrity of the striatum.
... Oxidative damage to biomolecules was followed by measuring lipid peroxidation and protein carbonyl formation in rat brain tissue culture over a period of 24 hr of exposure to /quinolinic acid/ at a concentration of 0.5 millimeters. Quinolinic acid enhanced lipid peroxidation in an early stage of tissue culture, and protein carbonyl at a later stage. ... Melatonin, an antioxidant and neuroprotective agent with multiple actions as a radical scavenger and signaling molecule, completely prevented these prooxidant actions of quinolinic acid at a concentration of 1 millimeters. Morphological lesions and neurotoxicity induced by quinolinic acid were evaluated by light microscopy. Quinolinic acid produced extensive apoptosis/necrosis which was significantly attenuated by melatonin. Cotreatment with melatonin exerted a profound protective effect antagonizing the neurotoxicity induced by quinolinic acid. Glutathione reductase and catalase activities were increased by quinolinic acid and these effects were antagonized by melatonin. Furthermore, melatonin induced superoxide dismutase activity. Quinolinic acid and melatonin acted independently and by different mechanisms in modulating antioxidant enzyme activities.
The neuroprotective effect of melatonin against the quinolinic acid-induced degeneration of rat hippocampal neurons was investigated. Three groups of rats were given intrahippocampal injections of either; saline, quinolinic acid or ip injections of melatonin prior to and after being injected with quinolinic acid. On the fifth day after the intrahippocampal injections the brains were removed and the hippocampi either sectioned and stained for microscopic examination or used in glutamate receptor binding studies. The results show that melatonin protects hippocampal neurons from quinolinic acid-induced neurodegeneration and partially prevents the decrease in glutamate receptor numbers caused by quinolinic acid. Thus, melatonin has the potential to reduce hippocampal neuronal damage induced by neurotoxins such as quinolinic acid. PMID:9704893
To study the effects of the caspase-1 inhibitor Ac-YVAD-CHO on quinolinic acid (QA)-induced apoptosis ... rats were pre-treated with intrastriatal infusion of Ac-YVAD-CHO (2-8 ug) before intrastriatal injection of QA (60 nmol). Striatal total proteins, genomic DNA, and nuclear proteins were isolated. The effects of Ac-YVAD-CHO on QA-induced caspase-1 activity, internucleosomal DNA fragmentation, IkappaB-alpha degradation, NF-kappaB, and AP-1 activation, and increases in p53 protein levels were measured with enzyme assays, agarose gel electrophoresis, electrophoresis mobility shift assays, and Western blot analysis. ... Pretreatment with Ac-YVAD-CHO inhibited QA-induced internucleosomal DNA fragmentation. Ac-YVAD-CHO inhibited QA-induced increases in caspase-1 activity and p53 protein levels, but had no effect on QA-induced IkappaB-alpha degradation, NF-kappaB or AP-1 activation. /The authors concluded that/ caspase-1 is involved in QA-induced p53 upregulation but not IkappaB-alpha degradation. Inhibition of caspase-1 attenuates QA-induced apoptosis in rat striatum.
For more Interactions (Complete) data for QUINOLINIC ACID (31 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 pyridinedicarboxylic acid that is pyridine substituted by carboxy groups at positions 2 and 3. It is a metabolite of tryptophan. It has a role as a NMDA receptor agonist, a human metabolite, a mouse metabolite and an Escherichia coli metabolite. It is a conjugate acid of a quinolinate(1-) and a quinolinate.
Quinolinic acid is a metabolite found in or produced by Escherichia coli (strain K12, MG1655).
Quinolinic acid has been reported in Homo sapiens, Garcinia mangostana, and other organisms with data available.
Quinolinic Acid is an intermediate product of the kynurenine pathway, which is responsible for the conversion of the amino acid tryptophan into nicotinamide adenine dinucleotide, with potential neurotoxic activity. If produced in excess, quinolinic acid can cross the blood-brain barrier (BBB) and function as an N-methyl-D-aspartate (NMDA) receptor agonist, which may lead to both neuronal damage and neurodegenerative brain disease. The NMDA receptor, a heterotetrameric, ligand-gated and voltage-dependent glutamate receptor, is critical for synaptic plasticity, learning and memory.
Quinolinic acid is a metabolite found in or produced by Saccharomyces cerevisiae.
A metabolite of tryptophan with a possible role in neurodegenerative disorders. Elevated CSF levels of quinolinic acid are correlated with the severity of neuropsychological deficits in patients who have AIDS.

---

Mechanism of Action
Huntington's disease is an autosomal dominant neurological disorder characterized by progressive chorea, cognitive impairment and emotional disturbance. The disease usually occurs in midlife and symptoms progress inexorably to mental and physical incapacitation. It has been postulated that an excitotoxin is involved in the pathogenesis of Huntington's disease. Schwarcz and colleagues have shown that quinolinic acid can produce axon-sparing lesions similar to those observed in Huntington's disease. The lesions result in a depletion of neurotransmitters contained within striatal spiny neurones, for example gamma-aminobutyric acid (GABA), while dopamine is unaffected. Recently, /several investigators/ ... demonstrated that in Huntington's disease striatum there is a paradoxical 3-5-fold increase in both somatostatin and neuropeptide Y which is attributable to selective preservation of a subclass of striatal aspiny neurones in which these peptides are co-localized. In the present study /the authors/ demonstrate that lesions due to quinolinic acid closely resemble those of Huntington's disease as they result in marked depletions of both GABA and substance P, with selective sparing of somatostatin/neuropeptide Y neurones. Lesions produced by kainic acid (KA), ibotenic acid (IA) and N-methyl-D-aspartate (MeAsp) were unlike those produced by quinolinic acid, as they affected all cell types without sparing somatostatin/neuropeptide Y neurones. These results suggest that quinolinic acid or a similar compound could be responsible for neuronal degeneration in Huntington's disease.
...To determine whether caspase cleavage of huntingtin is a key event in the neuronal dysfunction and selective neurodegeneration in Huntington's disease, /the authors/ generated YAC mice expressing caspase-3- and caspase-6-resistant mutant huntingtin. Mice expressing mutant huntingtin, resistant to cleavage by caspase-6 but not caspase-3, maintain normal neuronal function and do not develop striatal neurodegeneration. Furthermore, caspase-6-resistant mutant huntingtin mice are protected against neurotoxicity induced by multiple stressors including NMDA, quinolinic acid, and staurosporine. These results are consistent with proteolysis of huntingtin at the caspase-6 cleavage site being an important event in mediating neuronal dysfunction and neurodegeneration and highlight the significant role of huntingtin proteolysis and excitotoxicity in Huntington's disease.
... excitotoxic lesion of rat brain with the N-methyl-D-aspartate receptor agonist, quinolinic acid, induces expression of p53 messenger RNA and protein in brain regions showing delayed DNA fragmentation and that expression of p53 messenger RNA precedes DNA damage detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labelling. In addition, using in situ hybridization and immunocytochemistry we demonstrate 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 areas. Bax has been shown to promote neuronal death by interacting with Bcl-2 family members while Gadd-45 expression has been associated with suppression of the cell-cycle and DNA repair. These results suggest that p53 protein may function as an active transcription factor in lesioned brain perhaps initiating the re-expression of Bax in injured brain regions. However, since Gadd-45 precedes p53 expression it appears unlikely that p53 is involved in regulating the early expression of Gadd-45. Taken together however, these results suggest that p53, Bax and Gadd-45 may play important roles in the response (damage/recovery) of the brain following excitotoxic injury.
The kynurenine pathway is a major route of L-tryptophan catabolism leading to production of a number of biologically active molecules. Among them, the neurotoxin quinolinic acid, is considered to be involved in the pathogenesis of a number of inflammatory neurological diseases. ... Most of the approaches to explain the pathogenesis of Alzheimer's disease focus on the accumulation of amyloid beta peptide (A beta), in the form of insoluble deposits leading to formation of senile plaques, and on the formation of neurofibrillary tangles composed of hyperphosphorylated Tau protein. Accumulation of A beta is believed to be an early and critical step in the neuropathogenesis of Alzheimer's disease. There is now evidence for the kynurenine pathway being associated with Alzheimer's disease. Disturbances of the kynurenine pathway have already been described in Alzheimer's disease. Recently, /the authors/ demonstrated that A beta 1-42, a cleavage product of amyloid precursor protein, induces production of quinolinic acid, in neurotoxic concentrations, by macrophages and, more importantly, microglia. Senile plaques in Alzheimer's disease are associated with evidence of chronic local inflammation (especially activated microglia) A major aspect of quinolinic acid toxicity is lipid peroxidation and markers of lipid peroxidation are found in Alzheimer's disease. Together, these data imply that quinolinic acid may be one of the critical factors in the pathogenesis of neuronal damage in Alzheimer's disease. This review describes the multiple correlations between the kynurenine pathway and the neuropathogenesis of Alzheimer's disease and highlights more particularly the aspects of quinolinic acid neurotoxicity, emphasizing its roles in lipid peroxidation and the amplification of the local inflammation.
For more Mechanism of Action (Complete) data for QUINOLINIC ACID (15 total), please visit 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.

---

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.

---

View More

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.

---

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).

---

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