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PubMed1999

Depletion of systemic macrophages by liposome-encapsulated clodronate attenuates increases in brain quinolinic acid during CNS-localized and systemic immune activation.

Quinolinic acid is a neurotoxic tryptophan metabolite produced locally during immune activation. The present study tested the hypothesis that macrophages are an important source. In normal gerbils, the macrophage toxin liposome-encapsulated clodronate depleted blood monocytes and decreased quinolinic acid levels in liver (85%), duodenum (33%), and spleen (51%) but not serum or brain. In a model of CNS inflammation (an intrastriatal injection of 5 microg of lipopolysaccharide), striatal quinolinic acid levels were markedly elevated on day 4 after lipopolysaccharide in conjunction with infiltration with macrophages (lectin stain). Liposome-encapsulated clodronate given 1 day before intrastriatal lipopolysaccharide markedly reduced parenchymal macrophage invasion in response to lipopolysaccharide infusion and attenuated the increases in brain quinolinic acid (by 60%). A systemic injection of lipopolysaccharide (450 microg/kg) increased blood (by 38-fold), lung (34-fold), liver (23-fold), spleen (8-fold), and striatum (25-fold) quinolinic acid concentrations after 1 day. Liposome-encapsulated clodronate given 4 days before systemic lipopolysaccharide significantly attenuated the increases in quinolinic acid levels in blood (by 80%), liver (87%), spleen (80%), and striatum (68%) but had no effect on the increases in quinolinic acid levels in lung. These results are consistent with the hypothesis that macrophages are an important local source of quinolinic acid in brain and systemic tissues during immune activation.

Animals↗
PubMed1983

Differential vulnerability of central neurons of the rat to quinolinic acid.

Infusion of 120 nmol quinolinic acid into several regions of the rat's brain revealed differences in vulnerability to its neurotoxic effects, as judged by light microscopical analysis. The striatum, the pallidal formation and the hippocampus were the most susceptive brain areas whereas the cerebellum, substantia nigra, amygdala, medial septum and hypothalamus proved more resistant.

Animals↗
PubMed1976

On the induction of the hepatic tyrosine aminotransferase by quinolinic acid.

The induction of tyrosine aminotransferase by quinolinic acid is inhibited completely by cycloheximide and by alpha-amanitin, but only partially during the first 3 hours by 5-azacytidine and 8-azaguanine; longer treatment with 8-azaguanine, however, also prevents the major increase in enzyme activity. The hepatic concentration of cyclic AMP does not change after administration of quinolinic acid. Insulin, like hydrocortisone, acts additively to qlinolinic acid. The isoenzyme pattern of tyrosine aminotransferase is not changed cosniderably during induction of quinolinic acid. Most likely, quinolinic acid acts through its own mechanism of induction.

Amanitins↗
PubMed1999

Quinolinic acid, alpha-picolinic acid, fusaric acid, and 2,6-pyridinedicarboxylic acid enhance the Fenton reaction in phosphate buffer.

Quinolinic acid, alpha-picolinic acid, fusaric acid, and 2,6-pyridinedicarboxylic acid enhanced the Fenton reaction in phosphate buffer, respectively. The enhancement by quinolinic acid, alpha-picolinic acid, fusaric acid, and 2,6-pyridinedicarboxylic acid of the Fenton reaction may be partly related to their respective actions in the biological systems such as a neurotoxic effect (quinolinic acid), a marked growth-inhibitory action on rice seeding (alpha-picolinic acid and fusaric acid), and an antiseptic (2,6-pyridinedicarboxylic acid). The ultraviolet-visible absorption spectrum of the mixture of alpha-picolinic acid with ferrous ion showed a characteristic visible absorbance band with a lambda(max) at 443 nm, suggesting that alpha-picolinic acid chelate of Fe2+ ion forms in the solution. Similar characteristic visible absorbance band was also observed for the mixture of Fe2+ ion with quinolinic acid (or fusaric acid, or 2,6-pyridinedicarboxylic acid). The chelation seems to be related to the enhancement by quinolinic acid, alpha-picolinic acid, fusaric acid, and 2,6-pyridinedicarboxylic acid of the Fenton reaction. alpha-Picolinic acid was reported to be a toxic substance isolated from the culture liquids of blast mould (Piricularia oryzae CAVARA). On the other hand, it has also been known that chlorogenic acid protects rice plants from the blast disease. The chlorogenic acid inhibited the formation of the hydroxyl radical in the reaction mixture of alpha-picolinic acid, FeSO4(NH4)2SO4, and H2O2. Thus the inhibition may be a possible mechanism of the protective action of the chlorogenic acid against the blast disease.

Buffers↗
PubMed1989

[Effects of antagonists of exciting amino acids on the neuro-destructive effect of quinolinic acid in vitro in comparison with their anticonvulsive action in situ].

A comparative study of the influence of kynurenic acid (KYNA), L-kynurenine (KYN) and ethylimidazole-4-5-dicarboxylic acid (IEM-1442) on neuro-destructive effect of quinolinic acid (QUIN) in hippocampal cell cultures of mouse embryos and on convulsive action of QUIN after its injection into the brain ventricles of adult mice was performed. In presence of KYNA the neuronal destruction in vitro didn't occur under QUIN exposure, while in situ KYNA had no effect on convulsive action of QUIN. On the other hand, KYN and IEM-1442 didn't block the neurodegenerative action of QUIN in vitro, whereas in situ these compounds showed the anticonvulsant, effect. The results obtained suppose, that some anticonvulsants, preventing convulsive effects of QUIN, are not antagonists of the receptors, which mediate its neurodegenerative action.

Animals↗
PubMed1983

A new fluorometric assay method for quinolinic acid.

A new fluorometric assay method for quinolinic acid is introduced in this study. Quinolinic acid-hydrazine complex, a stable fluorescent compound, is formed after heating quinolinic acid with hydrazine at 215-220 degrees C for 2 min. Fluorescence excitation and emission maxima of the complex are at 285 and 380 nm, respectively. This assay method is rapid and rather sensitive. It takes about 30 min to ascertain the amount of quinolinic acid as low as 50 ng. Specificity of this method is high among biological compounds. An ultrasensitive assay method for quinolinic acid (as low as 20 pg) with diphenylhydrazine instead of hydrazine is also found. After separating the quinolinic acid-diphenylhydrazine complex from residual diphenylhydrazine, this ultrasensitive assay method may be practically applicable.

Chromatography, Thin Layer↗
PubMed1992

Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse.

Accumulation of quinolinic acid and neuroactive kynurenines derived from tryptophan are of potential significance in human neuropathologic diseases because of their neurotoxic and convulsant properties. Clinical studies have established that sustained elevations of quinolinic acid, L-kynurenine and kynurenic acid within the cerebrospinal fluid occur in patients with a broad spectrum of inflammatory diseases and correlate with markers of immune activation and interferon-gamma activity. The present study describes an animal model that replicates these clinical observations and investigates the role of interferon-gamma as a mediator between immune activation and increased kynurenine pathway metabolism. Marked elevations in quinolinic acid, L-kynurenine and 3-hydroxykynurenine as well as an increased ratio of quinolinic acid: kynurenic acid in brain occurred 24 h after systemic pokeweed mitogen administration to C57BL6 mice. In plasma, L-tryptophan and kynurenic acid levels were reduced by pokeweed mitogen, while the concentrations of L-kynurenine, 3-hydroxykynurenine and quinolinic acid were increased. Interferon-gamma, pokeweed mitogen and lipopolysaccharide induced indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway, and increased both L-kynurenine and quinolinic acid concentrations of brain and systemic tissues, particularly in the lung, gastrointestinal tract and spleen. In contrast, hepatic tryptophan-2,3-dioxygenase activity was either reduced or unaffected. Increases in kynurenine pathway metabolism were sustained in mice given daily injections of interferon-gamma for seven days and subsequent responses to interferon-gamma were further enhanced. In contrast, daily administration of lipopolysaccharide was associated with subsequent attenuated responsiveness (tolerance) to lipopolysaccharide, pokeweed mitogen and interferon-gamma. Systemic administration of a monoclonal antibody to mouse interferon-gamma either attenuated or abolished the responses of kynurenine pathway metabolism to pokeweed mitogen and interferon-gamma. We conclude that acute and chronic increases in quinolinic acid and neuroactive kynurenines follow immune stimulation in mice, and result from indoleamine-2,3-dioxygenase induction. The results demonstrate that interferon-gamma is an important mediator between immune stimulation and indoleamine-2,3-dioxygenase induction. These increases in kynurenine pathway metabolism closely parallel the responses documented in patients with a broad spectrum of inflammatory diseases. Mice treated with immune stimuli are a useful model to investigate the relationships between immune activation and kynurenine pathway metabolism.

Animals↗
PubMed1991

Differential complementary localization of metabolic enzymes for quinolinic acid in olfactory bulb astrocytes.

The cellular localizations of the synthetic [3-hydroxyanthranilic acid oxygenase (3HAO)] and degradative [quinolinic acid phosphoribosyltransferase (QPRT)] enzymes of the endogenous excitotoxin quinolinic acid were studied in the adult rat main olfactory bulb by immunohistochemical techniques. 3HAO and QPRT were expressed only in astrocytes. The two enzymes were differentially expressed by astrocytes in a complementary pattern: 3HAO staining was strongest at the glomerular-external plexiform layer junction; QPRT staining was strongest at the glomerular-olfactory nerve layer junction. The complementary distributions of these metabolic enzymes suggests that there could be a gradient of quinolinic acid across the glomerular layer of the main olfactory bulb. Such a gradient could function to restrict the ingrowth of new olfactory axons to the glomeruli and/or to stabilize the formation of new synapses.

3-Hydroxyanthranilate 3,4-Dioxygenase↗
PubMed1987

Transport of quinolinic acid into rabbit and rat brain.

The transport metabolism of [3H]quinolinic acid in the central nervous system of rabbits and rats were studied. In vitro [3H]quinolinic acid was not readily accumulated by isolated choroid plexus. After the intraventricular injection of tracer quantities of [3H]quinolinic acid, the [3H]quinolinic acid did not enter the brain as readily as concurrently injected [14C]mannitol and was not metabolized. The permeability-surface area constant for [3H]quinolinic acid at the rat blood-brain barrier was 1.5 +/- 1.3 X 10(-5) sec-1 compared to 2.8 +/- 0.4 X 10(-5) sec-1 for [3H]mannitol. Our results suggest that: 1) [3H]quinolinic acid is transported in the CNS by passive diffusion and 2) is not metabolized.

Animals↗
PubMed2003

Quinolinate dehydrogenase and 6-hydroxyquinolinate decarboxylase involved in the conversion of quinolinic acid to 6-hydroxypicolinic acid by Alcaligenes sp. strain UK21.

In the conversion of quinolinic acid to 6-hydroxypicolinic acid by whole cells of Alcaligenes sp. strain UK21, the enzyme reactions involved in the hydroxylation and decarboxylation of quinolinic acid were examined. Quinolinate dehydrogenase, which catalyzes the first step, the hydroxylation of quinolinic acid, was solubilized from a membrane fraction, partially purified, and characterized. The enzyme catalyzed the incorporation of oxygen atoms of H(2)O into the hydroxyl group. The dehydrogenase hydroxylated quinolinic acid and pyrazine-2,3-dicarboxylic acid to form 6-hydroxyquinolinic acid and 5-hydroxypyrazine-2,3-dicarboxylic acid, respectively. Phenazine methosulfate was the preferred electron acceptor for quinolinate dehydrogenase. 6-Hydroxyquinolinate decarboxylase, catalyzing the nonoxidative decarboxylation of 6-hydroxyquinolinic acid, was purified to homogeneity and characterized. The purified enzyme had a molecular mass of approximately 221 kDa and consisted of six identical subunits. The decarboxylase specifically catalyzed the decarboxylation of 6-hydroxyquinolinic acid to 6-hydroxypicolinic acid, without any co-factors. The N-terminal amino acid sequence was homologous with those of bacterial 4,5-dihydroxyphthalate decarboxylases.

Alcaligenes↗
PubMed1997

Activated human microglia produce the excitotoxin quinolinic acid.

We aimed to determine the relative role of quinolinic acid synthesis in purified human microglia, monocyte-derived macrophages and astrocytes in the human brain following immune stimulation. Microglia and macrophages significantly increased quinolinic acid synthesis from tryptophan following activation by either lipopolysaccharide or interferon-gamma. Quinolinic acid synthesis by individual microglia was heterogeneous, and its production by activated macrophages was approximately 32-fold greater than its microglial synthesis. Quinolinic acid synthesis by astrocytes was undetectable. Microglia may, therefore, be the primary endogenous cell type responsible for quinolinic acid synthesis in the brain parenchyma. However, under pathological conditions which precipitate blood-brain barrier compromise and/or leukocytic infiltration, intracerebral quinolinic acid may be derived chiefly from cells of the peripheral immune system such as activated macrophages.

Brain↗
PubMed1985

Dissociation between the excitatory and "excitotoxic" effects of quinolinic acid analogs on the striatal cholinergic interneuron.

Analogs of quinolinic acid were tested for excitatory properties in evoking neurotransmitter release from striatal cholinergic interneurons and for their ability to lesion these same neurons in vivo (excitotoxin activity). The ability of these analogs to inhibit the specific binding of several ligands thought to label excitatory amino acid receptors was also investigated. Dipicolinic acid (2,6-pyridine dicarboxylic acid) was found to be as potent and as efficacious as quinolinic acid (2,3-pyridine dicarboxylic acid) at N-methyl-D-aspartate (NMDA)-type receptors mediating [3H]acetylcholine release from striatal slices. However, unlike quinolinate, the structure of NMDA is not superimposable upon that of dipicolinic acid. Moreover, unlike quinolinic acid, dipicolinic acid injected intrastriatally did not produce detectable excitotoxic lesions. Most unexpectedly, phthalic acid (1,2-benzene dicarboxylic acid), which lacks a nitrogen, also evoked [3H]acetylcholine release from striatal slices, apparently by acting at NMDA-type receptors. Phthalic acid was equipotent to quinolinic acid and dipicolinic acid but possessed less intrinsic activity than these compounds in evoking [3H]acetylcholine release. Despite its lack of a nitrogen and low intrinsic activity, intrastriatal injection of phthalic acid produced axon-sparing lesions of intrinsic cell bodies, like quinolinic acid as assessed by neurochemical and histologic methods. Quinolinic acid, dipicolinic acid and phthalic acid were moderately potent inhibitors (Kl = approximately equal to 100 microM) of the specific binding of 2-[3H]amino-7-phosphonoheptanoic acid a compound thought to be a competitive antagonist of NMDA-type receptors. In contrast, these three compounds failed to inhibit the chloride-dependent or chloride-independent binding of L-[3H]glutamate or [3H]kainic acid. The present results suggest a major dissociation between the structure-activity relationships for "excitotoxicity" vis-à-vis excitation as reflected in the [3H]acetylcholine release model, for compounds acting at NMDA-type receptors.

Animals↗
PubMed2002

Enhanced neuronal damage by co-administration of quinolinic acid and free radicals, and protection by adenosine A2A receptor antagonists.

1. Quinolinic acid may be an important endogenous excitotoxin, but its concentrations in brain are low. We have therefore attempted to determine whether its neurotoxicity can be increased by the simultaneous presence of free radicals. 2. Quinolinic acid was injected into the hippocampus of anaesthetized rats at doses of 40 and 80 nmols which produced little neuronal loss, and 120 nmols which produced over 90% neuronal loss. 3. A mixture of xanthine and xanthine oxidase, a known source of free radical reactive oxygen species, also generated little damage alone, but killed over 80% of CA1 neurons when combined with 80 nmols of quinolinic acid. Similarly, the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) potentiated the damage produced by quinolinic acid. 4. The glutamate antagonist 5,7-dichlorokynurenic acid prevented the damage produced by 120 nmols of quinolinic acid, but not that produced by quinolinic acid plus xanthine/xanthine oxidase, indicating that damage was not simply the result of free radical enhancement of NMDA receptor activation. 5. Three chemically dissimilar antagonists at adenosine A(2A) receptors prevented the damage caused by quinolinic acid and xanthine/xanthine oxidase or by quinolinic acid plus SNAP. 6. It is concluded that reactive oxygen species can potentiate the neurotoxicity of quinolinic acid. The site of interaction is probably distal to the NMDA receptor. Blockade of adenosine A(2A) receptors can protect against this combined damage, suggesting potential value in the prevention of brain damage.

Animals↗
PubMed1991

Accumulation of quinolinic acid in uremic serum and its removal by hemodialysis.

Quinolinic acid was first identified in uremic serum by use of gas chromatography/mass spectrometry. Quantification by selected ion monitoring revealed that the serum concentration of quinolinic acid was markedly increased in chronic hemodialysis patients, and that the acid could be removed by conventional hemodialysis. The serum concentration of quinolinic acid was weakly but significantly correlated with the serum uric acid concentration. Accumulation of quinolinic acid in uremic blood may be involved in the pathogenesis of anemia, suppressed immune system, and uremic encephalopathy.

Adult↗
PubMed1988

Inhibition of quinolinate phosphoribosyl transferase by pyridine analogs of quinolinic acid.

The enzyme quinolinate phosphoribosyl transferase was purified from ATCC strain 23269. An HPLC method was developed for the analysis of the product of the enzyme reaction, nicotinate mononucleotide. Steady state kinetics in the forward reaction demonstrated a sequential mechanism for the enzyme. In order to gain more information on the mechanism of the enzyme reaction, a series of 2 substituted nicotinic acids and 2 substituted 3-nitropyridines were investigated as inhibitors of the reaction. The results indicate that potent inhibition results when the quinolinic acid analogs possessed a negatively charged group at the 2 position of the pyridine ring.

Chromatography, High Pressure Liquid↗
PubMed1997

Protective effects of neurotrophin-4/5 and transforming growth factor-alpha on striatal neuronal phenotypic degeneration after excitotoxic lesioning with quinolinic acid.

Lesioning of the mammalian striatum with the excitotoxin quinolinic acid results in a pattern of neuropathology that resembles that of post mortem Huntington's disease brain. Certain neurotrophic factors can rescue degenerating cells in a variety of lesion types, including those produced by neurotoxins. Several neurotrophic factors promote the survival of striatal neurons and/or are localized within the striatum. Of these factors, neurotrophin-4/5 and transforming growth factor-alpha were chosen for administration to rats lesioned with quinolinic acid. Adult rats received a single unilateral intrastriatal injection of quinolinic acid (120 nmol) and either trophic factors or the control protein cytochrome c for seven days thereafter. The pattern of phenotypic degeneration was assessed by immunocytochemical labeling of various striatal neuronal populations at five rostrocaudal levels. Quinolinic acid produced a preferential loss in the number of cells immunoreactive for glutamate decarboxylase, with a relative sparing of the number of choline acetyltransferase-immunoreactive cells and, to a lesser degree, calretinin-immunoreactive cells. None of these phenotypic populations was protected by either neurotrophin-4/5 or transforming growth factor-alpha. In contrast, when glutamate decarboxylase cells were alternatively identified by calbindin immunolabeling, both factors were found to have partially reversed the loss in the number of calbindin-positive cells induced by excitolesioning. In addition, the loss in the number of parvalbumin-immunopositive cells due to quinolinic acid was partially reversed by neurotrophin-4/5, while the loss in the number of NADPH-diaphorase-stained cells was partially reversed by transforming growth factor-alpha. These findings reveal a new population of striatal cells, calretinin neurons, that are relatively resistant to quinolinic acid toxicity and that neurotrophin-4/5 and transforming growth factor-alpha partially protect against the phenotypic degeneration of striatal cell populations in an in vivo animal model of Huntington's disease.

Animals↗
PubMedDate not supplied

[Effect of gamma-aminobutyric acid and its derivatives on convulsions induced by L-kynurenine and quinolinic acid].

Derivatives of GABA which are ineffective against seizures produced by typical convulsants (strychnine, pentylenetetrazole, etc.), phenibut and sodium hydroxybutyrate in doses of 200 mg/kg and higher possess marked anticonvulsant action against seizures induced by intraventricular injection of L-kynurenine and quinolinic acid in mice. Phepiron, a cyclic form of phenibut, had dissimilar action on the effects of L-kynurenine and a quinolinic acid, enhancing that produced by the former agent and diminishing tonic extension and lethality after the latter one. GABA and piracetam appeared to be ineffective. Efficacy of GABA derivatives against seizures produced by L-kynurenine and quinolinic acid suggests that the system of GABA plays a significant role in the genesis of seizures produced by kynurenines.

Animals↗