Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Quinolinic Acids”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 127 records · Page 7Linked to original sources
PubMed1999

Quinolinic acid in the cerebrospinal fluid of children after traumatic brain injury.

OBJECTIVE: To measure quinolinic acid, a macrophage-derived neurotoxin, in the cerebrospinal fluid (CSF) of children after traumatic brain injury (TBI) and to correlate CSF quinolinic acid concentrations to clinically important variables. DESIGN: A prospective, observational study. SETTING: The pediatric intensive care unit in Children's Hospital of Pittsburgh, a tertiary care, university-based children's hospital. PATIENTS: Seventeen critically ill children following severe TBI (Glasgow Coma Scale score <8) whose care required the placement of an intraventricular catheter for continuous drainage of CSF. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients ranged in age from 2 mos to 16 yrs (mean 6.0 yrs). CSF was collected immediately on placement of the ventricular catheter and daily thereafter. Quinolinic acid concentration was measured by gas chromatography/mass spectroscopy in 69 samples (4.0 +/- 0.4 [SEM] samples per patient). CSF quinolinic acid concentration progressively increased after injury (p = .034, multivariate analysis) and was increased in nonsurvivors vs. survivors (p = .002, multivariate analysis). CSF quinolinic acid concentration was not associated with age. Although overall CSF quinolinic acid concentration was not associated with shaken injury (p = .16, multivariate analysis), infants suffering with shaken infant syndrome had increased admission CSF quinolinic acid concentrations compared with children with accidental mechanisms of injury (p = .027, Mann-Whitney Rank Sum test). CONCLUSIONS: A large and progressive increase in the macrophage-derived neurotoxin quinolinic acid is seen following severe TBI in children. The increase is strongly associated with increased mortality. Increased CSF quinolinic acid concentration on admission in children with shaken infant syndrome could reflect a delay in presentation to medical attention or age-related differences in quinolinic acid production. These findings raise the possibility that quinolinic acid may play a role in secondary injury after TBI in children and suggest an interaction between inflammatory and excitotoxic mechanisms of injury following TBI.

Accidents, Traffic↗
PubMed1998

Chronic exposure of human neurons to quinolinic acid results in neuronal changes consistent with AIDS dementia complex.

OBJECTIVE: Concentrations of quinolinic acid, an N-methyl-D-aspartate agonist, are often elevated for long periods of time in the cerebrospinal fluid (CSF) and brain tissue of patients with AIDS dementia complex (ADC). This study was designed to test the hypothesis that chronic exposure of human neurons to quinolinic acid levels equivalent to those in the CSF of ADC patients is neurotoxic. DESIGN AND METHODS: Human fetal brain 14-16 weeks post-menses was cultured in medium with no detectable levels of quinolinic acid. After 4 weeks, 350 or 1200 nmol/l quinolinic acid was added to the feeding medium for a further 5 weeks. Neurotoxicity was evaluated using immunohistochemistry, transmission and scanning electron microscopy, and image analysis. RESULTS: A total of 1200 nmol/l quinolinic acid caused altered cell associations, a decrease in cell density and decreased microtubule-associated protein (MAP)-2 immunoreactivity compared with cultures exposed to 350 nmol/l quinolinic acid or controls. Image analysis of neurons in randomly selected fields revealed significantly swollen cells (P < 0.0001) compared with those treated with 350 nmol/l quinolinic acid or controls. Dendritic varicosities and discontinuous microtubular arrays were present in neurons exposed to both quinolinic acid concentrations, but not in control cultures. CONCLUSIONS: This study is the first to assess quinolinic acid levels in the experimental medium, and demonstrates that chronic exposure of human neurons to concentrations of quinolinic acid equivalent to those in the CSF of patients with ADC leads to alterations in dendritic ultrastructure and MAP-2 immunoreactivity, which is consistent with ADC pathology.

AIDS Dementia Complex↗
PubMed1997

Discriminable excitotoxic effects of ibotenic acid, AMPA, NMDA and quinolinic acid in the rat laterodorsal tegmental nucleus.

Excitotoxins are valuable tools in neuroscience research as they can help us to discover the extent to which certain neurones are necessary for different types of behaviour. They have distinctive neurotoxic effects depending on where they are infused, and this study was conducted to delineate the neurotoxic profiles of excitotoxins in the laterodorsal tegmental nucleus (LDTg). Two 0.1 microl infusions of 0.1 M ibotenate, 0.1 M quinolinate, 0.04-0.1 M NMDA, or 0.05-0.015 M AMPA, were made unilaterally into the LDTg under either pentobarbitone or Avertin anaesthesia. The injection needle was oriented at an angle of 24 degrees from vertical in the mediolateral plane. After 23-27 days, sections through the mesopontine tegmentum were processed using standard histological procedures for NADPH-diaphorase histochemistry, tyrosine hydroxylase or 5-hydroxytryptamine immunohistochemistry, and Cresyl violet. Lesions were assessed in terms of the size of the damaged area (identified by reactive gliosis), the extent of cholinergic cell loss in the mesopontine tegmentum (by counting NADPH-diaphorase-positive neurones), and neuronal loss induced in the locus coeruleus and dorsal raphe nucleus. Ibotenate induced compact lesions in the LDTg (more than 80% cholinergic loss) and did little damage to the locus coeruleus and dorsal raphe nucleus. Quinolinate and low doses of AMPA and NMDA made very small lesions with less than 35% cholinergic loss, while at higher doses, AMPA and NMDA induced large areas of reactive gliosis but killed only a proportion of the cholinergic neurones. AMPA appeared to have a particular affinity for noradrenergic neurones in the locus coeruleus, with the 0.015 M dose injected into the LDTg typically destroying the majority of these neurones. The results are discussed in the context of what is known about the mechanisms of excitotoxins and the glutamate receptor profile of mesopontine neurones.

Anesthetics↗
PubMed1985

Quinolinic acid phosphoribosyltransferase in rat brain.

Because of the possible participation of quinolinic acid in brain function and/or dysfunction, the characteristics of its catabolic enzyme, quinolinic acid phosphoribosyltransferase (QPRTase; EC 2.4.2.19), were examined in rat brain tissue. For this purpose, a sensitive radiochemical assay method, based on the conversion of quinolinic acid to nicotinic acid mononucleotide (NAMN), was developed. For brain QPRTase, the Mg2+ dependency, substrate specificity, and optimal assay conditions were virtually identical to those of the liver enzyme. Kinetic analyses of brain QPRTase revealed a Km of 3.17 +/- 0.30 microM for quinolinic acid and Km = 65.13 +/- 13.74 microM for the cosubstrate phosphoribosylpyrophosphate. The respective Vmax values were: 0.91 +/- 0.08 pmol NAMN/h/mg tissue for quinolinic acid and 11.65 +/- 1.55 fmol NAMN/h/mg tissue for phosphoribosylpyrophosphate. All kinetic parameters measured for the brain enzyme were significantly different from those determined for liver QPRTase, indicating structural differences or distinct regulatory processes for the brain and liver enzymes. Phthalic acid was a potent competitive inhibitor of brain QPRTase. Examination of the regional distribution of QPRTase in the rat CNS and retina indicated a greater than 20-fold difference between the area displaying the highest activity (olfactory bulb) and those of only moderate activity (frontal cortex, striatum, retina, hippo-campus). Enzyme activity was present at the earliest age tested, 2 days, and tended to increase in older animals. Brain QPRTase activity was preferentially located in the nerve-ending (synaptosomal) fraction. Enzyme activity was stable over extensive periods of storage at -80 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1984

The alteration of membrane proteins in human erythrocyte membranes induced by quinolinic acid, an endogenous neurotoxin. Correlation of effect with structure.

Quinolinic acid (2,3-pyridinedicarboxylic acid), an endogenous metabolite of L-tryptophan, reportedly via the kynurenine pathway, has been previously shown to possess neurotoxic properties when injected into rat striatum (Schwarcz, R., Whetsell, W.O., Jr. and Mangano, R.M. (1983) Science 219, 316-318) and to alter the physical state of human erythrocyte membrane proteins, as judged by ESR spectroscopy (Farmer, B.T., II and Butterfield, D.A. (1984) Life Sci. 35, 501-509). Both the morphologic and ESR studies employed nicotinic acid as one comparative control and found that the effect of quinolinic acid is significantly different from that of nicotinic acid. In the present study, we report that the effects of several structural analogues and positional isomers of quinolinic acid on the ESR parameter associated with the physical state of membrane proteins in human erythrocyte membranes suggest the following conclusions concerning the structure-effect relationship of quinolinic acid: The alteration in the conformation of membrane proteins: (1) requires the presence of two carboxylic acid groups; (2) is independent of their relationship to one another on the pyridine ring; (3) is slightly dependent on the presence of the pyridine nitrogen atom but is independent of the positional relationship of the two carboxylic acid moieties to the heteroatom; and (4) seems to depend upon the presence of restricted internal motion derived from the aromaticity in these compounds.

Electron Spin Resonance Spectroscopy↗
PubMed1996

Human microglia convert l-tryptophan into the neurotoxin quinolinic acid.

Immune activation leads to accumulations of the neurotoxin and kynurenine pathway metabolite quinolinic acid within the central nervous system of human patients. Whereas macrophages can convert L-tryptophan to quinolinic acid, it is not known whether human brain microglia can synthesize quinolinic acid. Human microglia, peripheral blood macrophages and cultures of human fetal brain cells (astrocytes and neurons) were incubated with [13C6]L-tryptophan in the absence or presence of interferon gamma. [13C6]Quinolinic acid was identified and quantified by gas chromatography and electron-capture negative-chemical ionization mass spectrometry. Both L-kynurenine and [13C6]quinolinic acid were produced by unstimulated cultures of microglia and macrophages. Interferon gamma, an inducer of indoleamine 2,3-dioxygenase, increased the accumulation of L-kynurenine by all three cell types (to more than 40 microM). Whereas large quantities of [13C6]quinolinic acid were produced by microglia and macrophages (to 438 and 1410 nM respectively), minute quantities of [13C6]quinolinic acid were produced in human fetal brain cultures (not more than 2 nM). Activated microglia and macrophage infiltrates into the brain might be an important source of accelerated conversion of L-tryptophan into quinolinic acid within the central nervous system in inflammatory diseases.

Astrocytes↗
PubMed1988

Systemic approaches to modifying quinolinic acid striatal lesions in rats.

Quinolinic acid (QA) is an endogenous excitotoxin present in mammalian brain that reproduces many of the histologic and neurochemical features of Huntington's disease (HD). In the present study we have examined the ability of a variety of systemically administered compounds to modify striatal QA neurotoxicity. Lesions were assessed by measurements of the intrinsic striatal neurotransmitters substance P, somatostatin, neuropeptide Y, and GABA. Histologic examination was performed with Nissl stains. The antioxidants ascorbic acid, beta-carotene, and alpha-tocopherol administered s.c. for 3 d prior to striatal QA lesions had no significant effect. Other drugs were administered i.p. 1/2 hr prior to QA striatal lesions. The following were ineffective in blocking QA excitotoxicity: allopurinol, 50 and 100 mg/kg; ketamine, 75 mg/kg; nimodipine, 2.4, and 10 mg/kg; baclofen, 10 mg/kg; 2-amino-5-phosphonovalerate, 50 mg/kg; and 2-amino-7-phosphonoheptanoate, 50 mg/kg. Oral taurine administration for 4 weeks resulted in significantly increased levels of brain taurine but had no significant effect in blocking QA neurotoxicity. Systemic administration of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 resulted in a dose-responsive protection against QA toxicity, with complete block at a dose of 4 mg/kg. If the pathogenesis of HD involves QA or another excitotoxin acting at the NMDA receptor, it is possible that MK-801 could retard the degenerative process.

2-Amino-5-phosphonovalerate↗
PubMed1989

Ion channels activated by quinolinic acid in cultured rat hippocampal neurons.

The membrane responses to quinolinic acid, an excitotoxic brain metabolite, were studied in cultured rat hippocampal neurons with the patch-clamp technique. In the whole-cell recording mode, pressure applications of quinolinic acid elicited inwardly directed membrane currents over a membrane potential range of -60 to -5 mV. The current response reversed at about 0 mV. The current-voltage (I-V) relation of the response had a negative slope conductance at membrane potentials more negative than -40 mV. On removal of Mg2+ from the extracellular solution, the current response showed no region of negative slope conductance at potentials more positive than -60 mV. In Mg2+-free solution applications of quinolinic acid elicited discrete pulse-like current flows through the outside-out membrane patch. The single channel conductance was 40-46 pS over a membrane potential range of -40 to -80 mV, and 50-55 pS at membrane potentials more positive than +30 mV, showing an outward rectification. These values of the single channel conductance were similar to those of the main conducting state of the channels activated by N-methyl-D-aspartate (NMDA). The responses to quinolinic acid were completely suppressed by the NMDA receptor antagonist (+/-)-2-amino-5-phosphonovaleric acid. The results indicate that quinolinic acid selectively activates NMDA receptors in the cultured rat hippocampal neurons.

2-Amino-5-phosphonovalerate↗
PubMed1990

Increased ratio of quinolinic acid to kynurenic acid in cerebrospinal fluid of D retrovirus-infected rhesus macaques: relationship to clinical and viral status.

Increased concentrations of excitotoxin quinolinic acid in cerebrospinal fluid (CSF) are associated with infection with the human immunodeficiency virus (HIV-1) and have been implicated in the pathogenesis of the acquired immune deficiency syndrome (AIDS) dementia complex. In the present study, inoculation of macaques with D/1/California, an immunosuppressive serotype 1 type D retrovirus, was associated with acute and chronic increases in CSF and serum quinolinic acid concentrations in macaques that had developed SAIDS, a simian disease analogous to AIDS in humans--particularly macaques with demonstrable opportunistic infections. Kynurenic acid, an antagonist of excitatory amino acid receptors as well as the excitotoxic effects of quinolinic acid, was also increased in the CSF of SAIDS macaques, but to a significantly lesser degree than was quinolinic acid (kynurenic acid, 1.8-fold; quinolinic acid, 15.6-fold). CSF quinolinic acid, but not kynurenic acid, was also increased in viremic macaques with SAIDS-related complex (2.4-fold) and asymptomatic virus positive carriers (3.4-fold). Macaques that had recovered from D/1/California infection and were antibody positive and virus negative had normal CSF quinolinic acid and kynurenic acid concentrations. Increased activity of indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway, was indicated in the macaques with SAIDS by reduced serum L-tryptophan and elevated serum L-kynurenine concentrations. Macaques infected with D/1/California may provide a primate model for investigation of the mechanisms involved in increases in CSF quinolinic acid in retrovirus and other infectious diseases, including HIV-1. It remains to be determined whether the increased CSF quinolinic acid concentrations and the increased ratio of quinolinic acid to kynurenic acid have neurological significance or are a useful "marker" of infection.

Animals↗
PubMed1989

Brain quinolinic acid in Alzheimer's dementia.

Quinolinic acid (QA) content was measured in postmortem frontal and temporal cortex, putamen and cerebellum obtained from patients with senile dementia of Alzheimer type (SDAT), Huntington's disease (HD) and controls, using a gas chromatography/mass spectrometry method. There were no significant group differences in QA content of any of the regions examined. The data do not support the hypothesis that an accumulation of QA plays a role in neuronal degeneration occurring in the frontal and temporal cortex, putamen and cerebellum of patients with SDAT.

Adult↗
PubMed1994

Nerve growth factor and basic fibroblast growth factor protect cholinergic neurons against quinolinic acid excitotoxicity in rat neostriatum.

In the present work we have characterized a possible mechanism leading to the early survival of neostriatal cholinergic neurons after quinolinic acid injection. Different doses of quinolinic acid were injected in rat neostriatum and two different parameters were analysed 7 days after the lesion: choline acetyltransferase (ChAT) activity and nerve growth factor (NGF) levels. We have observed that ChAT activity decreased (until 68 nmol quinolinic acid) and NGF levels increased (until 34 nmol quinolinic acid) in a dose-dependent manner. In order to characterize the time-course of the lesion on NGF levels and ChAT activity, and the possible protective effect of NGF and basic fibroblast growth factor (bFGF) on cholinergic neurons, we have used the quinolinic acid dose (68 nmol) at which the first decrease of ChAT activity was observed. ChAT activity and NGF levels showed different patterns of response to quinolinic acid injection, since the maximal effect was reached at 1 day for ChAT activity and at 2 days for NGF levels. NGF or bFGF simultaneously injected with quinolinic acid (68 nmol) completely prevented the decrease in ChAT activity in a dose-dependent manner but NGF was more effective than bFGF. Furthermore, differences observed in ChAT activity after NGF but not bFGF treatment were correlated with changes in the number of ChAT immunoreactive cells. Finally, we have also observed that, although bFGF alone was not able to modify NGF levels, bFGF simultaneously injected with quinolinic acid produced an increase of NGF levels higher than that observed after quinolinic acid injection alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Immunocytochemical localization of the quinolinic acid synthesizing enzyme, 3-hydroxyanthranilic acid oxygenase, in the rat substantia nigra.

Quinolinic acid, an endogenous excitatory amino acid receptor agonist, may play a role in several brain diseases. In the present study, the immunocytochemical localization of 3-hydroxyanthranilic acid oxygenase (3HAO), the enzyme responsible for the synthesis of quinolinic acid, was examined in the adult rat substantia nigra at the light and electron microscopic levels. 3HAO-immunoreactivity was detected exclusively in astrocytes. Labeling was present in cell bodies and in fine glial processes, which frequently encircled capillaries and partially enveloped neuronal somata. Notably, 3HAO-labeled processes were in close contact with several types of synaptic profiles. Often, they partially engulfed asymmetric synapses, characteristic of excitatory neurotransmission. In addition, they were found in apposition to putative dopaminergic cell bodies. These data provide an anatomical basis for the idea that functional interactions may occur between glial processes which synthesize quinolinic acid, and synaptic profiles, many of which presumably utilize excitatory neurotransmitters.

3-Hydroxyanthranilate 3,4-Dioxygenase↗
PubMed1992

Relationship of neurologic status in macaques infected with the simian immunodeficiency virus to cerebrospinal fluid quinolinic acid and kynurenic acid.

Increased concentrations of the excitotoxin quinolinic acid (QUIN) have been implicated in the neurologic deficits and brain atrophy that may accompany infection with the human immunodeficiency virus type-1. Key neuropathologic features of the AIDS encephalitis are replicated in some macaques following infection with the simian immunodeficiency virus (SIV). In the present studies, cerebrospinal fluid (CSF) QUIN concentrations increased within 2 weeks following infection of 11 rhesus macaques (Macaca mulatta) with a neurotropic sooty mangabey isolate of the simian immunodeficiency virus (SIVsm) and were sustained to greater than 2 standard deviations above uninfected control macaques. Highest CSF QUIN concentrations (up to 400-fold above pre-inoculation levels) were observed in 6 SIVsm-infected macaques with motor and behavioral abnormalities during life, brain atrophy on MRI scan and inflammatory lesions within the brain and meninges. Four of the 6 neurologic macaques deteriorated rapidly within 12 weeks after inoculation and had substantially larger increases in CSF QUIN levels than 2 other neurologic macaques and 5 macaques without neurologic signs which survived for longer than 37 weeks. Increases in serum QUIN and CSF kynurenic acid also occurred but generally to a lesser degree than the increases in CSF QUIN. In some animals, increases in serum L-kynurenine concentrations and reductions in CSF and serum L-tryptophan occurred and were consistent with activation of indoleamine-2, 3-dioxygenase, the first enzyme of the kynurenine pathway in extrahepatic tissues. CSF QUIN exceeded serum QUIN in 8.8% of samples from macaques with neurologic signs, supporting increased QUIN synthesis within the central nervous system. Production of [13C6]QUIN was demonstrated in one SIVsm-infected macaque and one uninfected control macaque following an intracisternal injection of [13C6]L-tryptophan and suggests that L-tryptophan is a substrate for QUIN synthesis within the nervous system or meninges, although the cellular localization of QUIN synthesis remain to be determined. We conclude that increases in kynurenine pathway metabolism occur in SIV-infected macaques and are most prominent in macaques with neurologic signs. Macaques infected with SIV offer a model to investigate the relationship between the metabolism of neuroactive kynurenines and neurologic disturbances associated with retroviral infection.

Animals↗
PubMed1983

On the excitotoxic properties of quinolinic acid, 2,3-piperidine dicarboxylic acids and structurally related compounds.

To obtain information about the receptors which mediate the neurotoxic actions of quinolinic acid, a series of pyridine dicarboxylates and piperidine dicarboxylates and structurally related compounds were tested for their neurotoxic effects following intrastriatal or intrahippocampal infusion in the rat, and for their activity in assays of binding and uptake sites for acidic amino acids. Of the compounds tested, only cis- and trans-2,3-piperidine dicarboxylates and quinolinic acid showed pronounced neurotoxic effects. At 600 nmol, 2,6- and 3,4-pyridine dicarboxylates were weakly active and the remaining compounds were inactive in both brain regions. After injection into the striatum of the adult rat, trans-2,3-piperidine dicarboxylate, quinolinic acid and cis-2,3-piperidine dicarboxylate caused axon-sparing neuronal degeneration as assessed by light microscopic and neurochemical methods, the threshold doses being 12, 24 and 120 nmol, respectively. In the striatum of the 7-day old rat, 30 nmol quinolinic acid or 600 nmol cis-2,3-piperidine dicarboxylate were inactive. Small doses of cis-2,3-piperidine dicarboxylate (60 nmol) and quinolinic acid (30 nmol) injected into the adult rat hippocampus resulted in a preferential loss of pyramidal neurons. In larger doses granule cells also degenerated. In contrast, trans-2,3-piperidine dicarboxylate was equally toxic to hippocampal neurons, regardless of the dose used. No "distant" neuronal damage was observed after the intracerebral application of any test compound. Equimolar amounts of (-)-2-amino-7-phosphonoheptanoic acid completely blocked the neurotoxic effects of quinolinic acid, cis- and trans-2,3-piperidine dicarboxylate after injection into the striatum or hippocampus. None of the analogs tested were good inhibitors of Cl--dependent or independent binding of L-[3H]glutamate, [3H]kainate or high-affinity, Na+-dependent uptake of L-glutamate in striatal or hippocampal tissue at 1 mM. The results indicate that the receptors mediating the neurotoxic effects of these compounds have strict structural requirements for activation. Whereas the excitotoxic characteristics of trans-2,3-piperidine dicarboxylate suggest a direct action on N-methyl-D-aspartate receptors, the properties of quinolinic acid and cis-2,3-piperidine dicarboxylate are far more complex and make categorization of their receptor-interactions difficult. Indirect mechanisms may account for the excitotoxicity of quinolinic acid and cis-2,3-piperidine dicarboxylate.

Animals↗
PubMed1993

4-Chloro-3-hydroxyanthranilate, 6-chlorotryptophan and norharmane attenuate quinolinic acid formation by interferon-gamma-stimulated monocytes (THP-1 cells).

Accumulation of quinolinic acid and L-kynurenine occurs in the brain and/or blood following immune activation, and may derive from L-tryptophan following induction of indoleamine 2,3-dioxygenase and other kynurenine-pathway enzymes. In the present study a survey of various cell lines derived from either brain or systemic tissues showed that, while all cells examined responded to interferon-gamma by increased conversion of L-[13C6]tryptophan into L-kynurenine (human: B-lymphocytes, neuroblastoma, glioblastoma, lung, liver, kidney; rat brain: microglia, astrocytes and oligodendrocytes), only macrophage-derived cells (peripheral-blood mononuclear cells; THP-1, U-937) and certain liver cells (SKHep1) synthesized [13C6]quinolinic acid. Tumour necrosis factor-alpha enhanced the effects of interferon-gamma in THP-1 cells. Norharmane, 6-chloro-DL-tryptophan and 4-chloro-3-hydroxyanthranilate attenuated quinolinic acid formation by THP-1 cells with IC50 values of 51 microM, 58 microM and 0.11 microM respectively. Norharmane and 6-chloro-DL-tryptophan attenuated L-kynurenine formation with IC50 values of 43 microM and 51 microM respectively, whereas 4-chloro-3-hydroxyanthranilate had no effect on L-kynurenine accumulation. The reductions in L-kynurenine and quinolinic acid formation are consistent with the reports that norharmane is an inhibitor of indoleamine 2,3-dioxygenase, 6-chloro-DL-tryptophan is metabolized through the kynurenine pathway, and 4-chloro-3-hydroxyanthranilate is an inhibitor of 3-hydroxyanthranilate 3,4-dioxygenase. These results suggest that many tissues may contribute to the production of L-kynurenine following indoleamine 2,3-dioxygenase induction and immune activation. Quinolinic acid may be directly synthesized from L-tryptophan in both macrophages and certain types of liver cells, although uptake of quinolinic acid precursors from blood may contribute to quinolinic acid synthesis in cells that cannot convert L-kynurenine into quinolinic acid.

3-Hydroxyanthranilic Acid↗
PubMed1991

Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological status.

Quinolinic acid is an "excitotoxic" metabolite and an agonist of N-methyl-D-aspartate receptors. Of patients infected with human immunodeficiency virus type 1 (HIV-1) who were neurologically normal or exhibited only equivocal and subclinical signs of the acquired immunodeficiency syndrome (AIDS) dementia complex, concentrations of quinolinic acid in cerebrospinal fluid (CSF) were increased twofold in patients in the early stages of disease (Walter Reed stages 1 and 2) and averaged 3.8 times above normal in later-stage patients (Walter Reed stages 4 through 6). However, in patients with either clinically overt AIDS dementia complex, aseptic meningitis, opportunistic infections, or neoplasms, CSF levels were elevated over 20-fold and generally paralleled the severity of cognitive and motor dysfunction. CSF concentrations of quinolinic acid were significantly correlated to the severity of the neuropsychological deficits. After treatment of AIDS dementia complex with zidovudine and treatment of the opportunistic infections with specific antimicrobial therapies, CSF levels of quinolinic acid decreased in parallel with clinical neurological improvement. By analysis of the relationship between levels of quinolinic acid in the CSF and serum and integrity of the blood-brain barrier, as measured by the CSF:serum albumin ratio, it appears that CSF levels of quinolinic acid may be derived predominantly from intracerebral sources and perhaps from the serum. While quinolinic acid may be another "marker" of host- and virus-mediated events in the brain, the established excitotoxic effects of quinolinic acid and the magnitude of the increases in CSF levels of the acid raise the possibility that quinolinic acid plays a direct role in the pathogenesis of brain dysfunction associated with HIV-1 infection.

AIDS Dementia Complex↗
PubMed1983

Quinolinic acid: regional variations in neuronal sensitivity.

The excitatory action of quinolinic acid has been examined on neurons in different parts of the rat CNS. When applied by microiontophoresis quinolinic acid excited cells in the cerebral cortex, hippocampus and neostriatum, but even when applied from electrodes which produced responses in these areas, quinolinic acid was ineffective in the cerebellum and spinal cord. Like most excitants tested in other studies, L-glutamate was excitatory to all cells examined. As an endogenous compound, therefore, quinolinic acid may merit special attention as a potential neurotransmitter in brain.

Animals↗
PubMed1978

Effects of quinolinic acid and glucagon on gluconeogenesis in the perfused rat liver.

Previous findings that 2.5 mM quinolinic acid inhibits gluconeogenesis more strongly from alanine than from lactate have been confirmed. 15 mM quinolinic acid completely inhibited gluconeogenesis from lactate as well as from alanine whereas the formation of glucose from fructose and the production of urea from ammonia and lactose were not affected. The pattern of the gluconeogenic intermediates was the same in the presence of 15 mM quinolinic acid as with 2.5 mM of the inhibitor. It is concluded that high as well as low concentrations of quinolinic acid inhibit gluconeogenesis at the step between oxaloacetate and phosphoenolpyruvate. Furthermore, 5-methoxyindole-2-carboxylic acid, an inhibitor of mitochondrial pyruvate metabolism, also completely blocked gluconeogenesis from lactate whereas glycerol conversion to glucose was only weakly inhibited. All these results do not support the concept of an alternate pathway of gluconeogenesis from lactate proposed by others. 2.5 mM quinolinic acid also partially blocked the formation of urea from alanine. It is suggested that quinolinic acid may have a second site of action causing an inhibition of the glutamate-pyruvate transamination owing to lack of 2-oxoglutarate in the cytosol. In the presence of quinolinic acid, glucagon caused about the same increase in aspartate and malate tissue levels in the absence of added substrates as in the presence of added lactate or alanine. Therefore, no additional effect of glucagon on gluconeogenesis from lactate or alanine prior to the block by quinolinic acid could be demonstrated.

Alanine↗