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At least 19 recordsLinked to original sources
PubMed1989

The effects of kynurenic acid, quinolinic acid and other metabolites of tryptophan on the development of the high pressure neurological syndrome in the rat.

The effects of some biologically active metabolites of tryptophan on the high pressure neurological syndrome (HPNS) were studied. Kynurenic acid, quinolinic acid, 5-hydroxytryptophan, kynurenine and 3-hydroxyanthranilic acid, at doses within the physiological range, were administered exogenously to rats prior to exposure to increased pressure and any effects on the tremor, myoclonus and convulsion end points of the high pressure neurological syndrome were observed. Quinolinic acid (25 and 50 mg/kg) and kynurenine (50 mg/kg) reduced the onset pressure for tremor, but not myoclonus or convulsions. Kynurenic acid (100 mg/kg) increased tremor onset pressure; 5-hydroxytryptophan (20 mg/kg) slightly increased onset pressure for tremor but decreased that for myoclonus. 3-Hydroxyanthranilic acid (20 mg/kg) had no significant effect on any of the motor signs of the syndrome. These data provide further support for the idea that the motor events seen in the high pressure neurological syndrome are not produced by a single mechanism. Differences between the responses to related metabolites suggest that the precise balance between compounds such as kynurenic acid and quinolinic acid may be important in the appearance of the high pressure neurological syndrome.

Animals↗
PubMed1985

Quinolinic acid neurotoxicity in the nucleus basalis antagonized by kynurenic acid.

Quinolinic acid, a metabolite of tryptophan, behaves as an excitotoxic amino acid. It has been proposed that quinolinic acid might be implicated in neurodegenerative diseases. The related metabolite, kynurenic acid, has been found to be a powerful antagonist of quinolinic acid. The ability of quinolinic acid, alone or in combination with kynurenic acid, to destroy cholinergic neurons projecting to the cortex was examined by morphological and biochemical criteria. The compounds were injected unilaterally into the nbm of the rat. Neuronal destruction of the basal forebrain occurred with quinolinic acid alone; however, no cell loss was observed when kynurenic and quinolinic acid were co-injected. Quinolinic acid lesions of the nucleus basalis caused significant decreases in cortical choline acetyltransferase, acetylcholinesterase, high affinity choline uptake and 3H-acetylcholine release. These reductions in cortical cholinergic markers were prevented by co-injecting kynurenic with quinolinic acid. A significant decrease in cortical choline acetyltransferase activity was observed three months following quinolinic acid lesions of the nucleus basalis. The results indicate that quinolinic acid can be used as an endogenous neurotoxin to produce lesions of the nbm resulting in impaired cortical cholinergic function similar to that seen in Alzheimer's disease.

Acetylcholinesterase↗
PubMed1989

[Morphological picture of lesions to substantia nigra of rats following intracardial administration of quinolinic acid].

Quinolinic acid is tryptophan metabolite and one of the known endogenous substance of selective neurotoxic properties. Morphological studies on noxious effect of quinolinic acid on the black substance of the brain of rats following intracardial administration of this acid were carried out. Dependence of the lesions on the dose and time of use were analysed. No lesions to the black substance were noted following a series of everyday injections of quinolinic acid in the dose of 30 mol/ml for 4 and 8 days. Degenerative changes in the neurons of black substance appeared after a dose of 60 mol/ml injected everyday for 4 days. These changes exacerbated significantly after 8 days. Generalized neuronal defects and intensive degenerative lesions in the preserved neurons with signs of decomposition of fibrous elements of tissular basis followed an administration of quinolinic acid in the dose of 100 mol/ml for 4 and 8 consecutive days.

Animals↗
PubMed1988

Localization of quinolinic acid metabolizing enzymes in the rat brain. Immunohistochemical studies using antibodies to 3-hydroxyanthranilic acid oxygenase and quinolinic acid phosphoribosyltransferase.

Specific antibodies raised in rabbits against 3-hydroxyanthranilic acid oxygenase (EC 1.13.11.6) and quinolinic acid phosphoribosyltransferase (EC 1.13.11.6) and quinolinic acid phosphoribosyltransferase (EC 2.4.2.19) were used in immunohistochemical studies to map the cellular localization of the quinolinic acid metabolizing enzymes in the adult male rat brain. 3-Hydroxyanthranilic acid oxygenase immunoreactivity was found to be present in glial cells of presumed astroglial identity, as judged by co-localization with glial fibrillary acidic protein. 3-Hydroxyanthranilic acid oxygenase-immunoreactive glial cells were present in all brain regions and within major fiber tracts. The density of 3-hydroxyanthranilic acid oxygenase-immunoreactive glial cells as well as the intensity of staining of these cells differed among brain regions. In general, telencephalic acid diencephalic areas harbored a larger number of 3-hydroxyanthranilic acid oxygenase-positive cells than did mesencephalic regions. In the former regions the caudate nucleus, septum, nucleus accumbens, neocortex and hippocampus were particularly enriched in 3-hydroxyanthranilic acid oxygenase-immunoreactive cells. In the thalamus, regional differences were noted with regard to the intensity of staining among glial cells with high densities of 3-hydroxyanthranilic acid oxygenase cells in the anteroventral, reticular and ventromedial nuclei. In the inferior and superior colliculi, numerous 3-hydroxyanthranilic acid oxygenase-positive glial cells were found in all layers. In the hypothalamus, 3-hydroxyanthranilic acid oxygenase-immunoreactive glial cells were encountered in the zona incerta, the lateral hypothalamic area, the caudal preoptic region and in the dorsomedial nucleus. In the mesencephalon, the substantia nigra contained numerous, moderately stained cells. At caudal levels of the brain-stem, a relatively large number of cells was detected in the nucleus of the solitary tract, the pontine nucleus and in the fascial nerve nucleus, while other nuclei, such as the reticular formation and the area postrema were relatively poor in 3-hydroxyanthranilic acid oxygenase-immunoreactive cells. In addition to staining of glial cells, neuronal cell bodies containing 3-hydroxyanthranilic acid oxygenase immunoreactivity were detected in the main and in the accessory olfactory bulb, as well as in the ventromedial nucleus of the hypothalamus. Quinolinic acid phosphoribosyltransferase immunoreactivity was observed within glial cells and in association with neuronal cell bodies. Some, but not all, quinolinic acid phosphoribosyltransferase positive glial cells contained glial fibrillary acidic protein (Köhl

3-Hydroxyanthranilate 3,4-Dioxygenase↗
PubMed1991

Nerve cell death induced in vivo by kainic acid and quinolinic acid does not involve apoptosis.

We investigated whether in vivo excitotoxicity was mediated by a mechanism of programmed cell death called apoptosis. Neurotoxic doses of kainic acid (1.2 nmol) and quinolinic acid (120 nmol) were unilaterally injected in the dorsal hippocampus of anesthetized rats. Eight or 16 h later the animals were killed and DNA was extracted from the injected hippocampi. DNA from mouse thymocytes exposed to methylprednisolone (10(-5) M for 6 h at 37 degrees C) was used as a positive control of apoptotic cells. No typical 'ladder' of DNA fragments (multimers of approximately 200 Kb) which characterizes apoptosis was seen in hippocampal cells after toxic doses of kainic or quinolinic acid, as assessed by agarose gel electrophoresis. This suggests that hippocampal nerve cell death induced in vivo by the excitotoxins is not mediated by apoptosis.

Animals↗
PubMed1988

Quinolinic acid metabolism in the rat brain. Immunohistochemical identification of 3-hydroxyanthranilic acid oxygenase and quinolinic acid phosphoribosyltransferase in the hippocampal region.

Quinolinic acid (QUIN) is a potent endogenous excitotoxin, which has been shown to be present in the brain (Wolfensberger et al., 1983). In order to study the cellular localization of QUIN metabolism in the hippocampus, specific antibodies raised against purified rat liver 3-hydroxyanthranilic acid oxygenase (3HAO) and quinolinic acid phosphoribosyltransferase (QPRT), the enzymes directly responsible for QUIN synthesis and catabolism, respectively, were used for immunohistochemical studies in the adult male rat. Cells containing 3HAO immunoreactivity (3HAO-i) were present in all subfields of the hippocampal region, including the area dentata, Ammon's horn, the subicular complex, and the entorhinal area. The highest density of 3HAO-i cells was found in the molecular layer of Ammon's horn and in the hilus of area dentata, while the granular cell layer of area dentata and stratum pyramidale of Ammon's horn contained the lowest number of 3HAO-stained cells. A majority of hippocampal 3HAO-i cells were also stained with monoclonal antibodies against glial fibrillary acidic protein (GFAP) or S-100 protein, suggesting that 3HAO-i is present primarily in astrocytes. At the ultrastructural level, 3HAO-i was found to be distributed uniformly throughout the cytoplasm, with intense immunostaining present in the internal and the external layers of the mitochondria. QPRT-i was detected in 3 morphologically distinct cell types present in all parts of the hippocampus. The total number of QPRT-i cells was lower than that of the 3HAO-i cells. QPRT-i cells were relatively numerous in the molecular and radial layers of Ammon's horn, while they occurred only sporadically in stratum pyramidale of Ammon's horn and in the granular cell layer of area dentata. Many QPRT-i cells stained with antibodies against GFAP and S-100, but the proportion of cells in which QPRT was colocalized with these glial marker proteins was lower than that for 3-HAO-i cells. At the ultrastructural level, 2 types of QPRT-i glial cells were detected. The smaller cell type had a diffuse cytoplasmic staining, while the larger cell type, which also contained glial filaments, showed diffuse cytoplasmic staining and intense staining of lysosomal structures. The observation that 3HAO and QPRT only partially coexist in hippocampal glial cells suggests that while synthesis and catabolism of QUIN may occur in the same glial cells, catabolism of QUIN can also take place in cells lacking the synthetic enzyme.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

[Selective anticonvulsive action of N-substituted imidazole-4,5-dicarboxylic acids against quinolinic acid].

Selective antagonists of quinolinic acid (2,3-pyridine dicarboxylic acid, QUIN)--an endogenous convulsant tryptophan metabolite, administered intracerebroventricular to mice, were identified during comparison with the following intracerebroventricular convulsants: l-kynurenine, aspartic, glutamic, N-methyl-DL-aspartic and kainic acids. It is suggested that the antagonism arises due to a common fragment of the structure which consists of two carboxylic groups at two nearest carbon atoms of the ring and of one nitrogen atom in the alpha-position. The selective action of the compounds found against QUIN supports the suggestion that QUIN produces seizures via N-methyl-D-aspartate binding sites.

Animals↗
PubMed1987

Effects of 2,4,5-trichlorophenoxyacetic acid and quinolinic acid on 5-hydroxy-3-indoleacetic acid transport by the rabbit choroid plexus: pharmacology and electron microscopic cytochemistry.

2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) reduced the uptake of 5-hydroxy-3-indoleacetic acid (5-HIAA) by the choroid plexus in a dose-related manner, while treatment with quinolinic acid at comparable concentrations did not inhibit 5-HIAA uptake. The role of carrier-mediated transport in the clearance of 5-HIAA from cerebrospinal fluid (CSF) was also evaluated in vivo by ventriculocisternal perfusion. Steady-state clearance of 5-HIAA from CSF exceeded that of inulin and was reduced competitively in the presence of 2,4,5-T. However, the clearance was not affected by quinolinic acid. The effect of 2,4,5-T on transport enzyme systems was also studied by electron microscopic cytochemistry. Na+-K+-ATPase and cytochrome oxidase activities in the choroid plexus were reduced by 2,4,5-T. Since this transport system in the choroid plexus is normally responsible for the excretion of the serotonin metabolite from the brain to the plasma, accumulation of endogenously produced organic acids in the CSF and the brain, secondary to reduced clearance by the choroid plexus, could be a contributing factor in the development of neurotoxicity.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1989

Alteration of kainic acid and quinolinic acid toxicity by neostriatal transplants in vitro.

Mature (greater than 21 days in vitro) organotypic corticostriatal cultures prepared from newborn rat brain were incubated in either kainic acid (KA) 10(-3) M or quinolinic acid (QUIN) 10(-3) M for up to 48 h. Other identical cultures were similarly incubated immediately after they had received one or two additional explants of neonatal striatal tissue placed beside each corticostriatal culture. The cultures incubated with either KA or QUIN in the presence of the neonatal striatal tissue showed better preservation than cultures incubated with KA or QUIN alone. Results suggest that the neonatal striatal explants or 'transplants' afford some protective effect against the toxicity or either KA or QUIN.

Animals↗
PubMed1985

Actions of kynurenic acid and quinolinic acid in the rat hippocampus in vivo.

An iontophoretic study was made of the interaction of kynurenic acid with excitatory amino acids in the hippocampus and with the commissural input from the contralateral hippocampus in the rat. The results showed that kynurenic acid was an effective blocker of synaptic transmission in the hippocampus in vivo, adding further support to the idea that an excitatory amino acid is involved in neurotransmission in this structure. In addition there was an increase in the specificity of kynurenate as an antagonist of excitatory amino acids in the hippocampus compared with neocortex, with much more activity being shown toward the NMDA-preferring rather than the quisqualic acid-preferring receptor. Kynurenic acid was also able to distinguish partially between quinolinic acid and NMDA, supporting the possibility that two types of NMDA/quinolinate receptors exist in the hippocampus.

Amino Acids↗
PubMed1986

Kynurenic acid and quinolinic acid act at N-methyl-D-aspartate receptors in the rat hippocampus.

Responses evoked by several amino acid excitants, including the tryptophan metabolite quinolinic acid, were recorded intracellularly from CA1 pyramidal neurons in rat hippocampal slices. Quinolinate, N-methyl-D-aspartate (NMDA), ibotenate and (+/-)-cis-1-amino-1,3-dicarboxycyclopentane produced excitations characterized by burst firing of action potentials, tetrodotoxin-resistant spiking and apparent increases in input resistance measured with brief hyperpolarizing current pulses. L-Glutamate, kainate, quisqualate and (+/-)-2'-amino-3-hydroxy-5-methyl-4-isoxazole-3'-propionate depolarized CA1 pyramidal neurons and induced apparent decreases in input resistance. Quinolinate-, NMDA-, and ibotenate-induced focal depolarizations, but not L-glutamate, kainate- or quisqualate-induced responses, were strongly antagonized by specific NMDA receptor antagonists. The tryptophan metabolite kynurenic acid, at concentrations that antagonized focal depolarizations produced by NMDA, ibotenate and the endogenous excitant quinolinate, did not antagonize quisqualate or L-glutamate responses. In addition to its NMDA-type antagonist action, kynurenate blocked kainate-induced focal depolarizations.

Animals↗
PubMed1986

Ca2+-dependent depolarization and burst firing of rat CA1 pyramidal neurones induced by N-methyl-D-aspartic acid and quinolinic acid: antagonism by 2-amino-5-phosphonovaleric and kynurenic acids.

The excitatory effects of microiontophoretically applied quisqualic (QUIS), N-methyl-D-aspartic (NMDA), and quinolinic (QUIN) acids were investigated using intracellular recording from CAl pyramidal neurones in slices of rat hippocampus. QUIS evoked only simple action potentials superimposed upon a depolarization which attained a clear plateau. When this level had been reached, increased ejecting currents did not produce further depolarization. By contrast, with low currents NMDA and QUIN elicited small membrane depolarizations which triggered bursts of action potentials superimposed upon rhythmically occurring depolarizing shifts. Larger currents caused depolarization which if sufficiently large completely blocked spike activity. Tetrodotoxin (TTX) prevented the spikes evoked by QUIS and the bursts of action potentials seen with NMDA and QUIN, and the rhythmic depolarizing shifts then appeared as broad spikes of up to 50 mV in amplitude. These and the underlying membrane depolarization were blocked by Co2+, by the NMDA antagonist D(-)-2-amino-5-phosphonovaleric acid (DAPV), and by kynurenic acid (KYNU). It thus appears that the depolarization and burst firing of rat CAl pyramidal neurones elicited by NMDA and QUIN are Ca2+ dependent while the actions of QUIS are not.

2-Amino-5-phosphonovalerate↗
PubMed1985

Effects of intracerebral injections of quinolinic acid on serotonergic neurons in the rat brain.

The effects of intrastriatal and intrahippocampal injections of the excitotoxic amino acid, quinolinic acid (QUIN), were examined in the rat using immunohistochemical and neurochemical techniques. Serotonin and 5-hydroxyindoleacetic acid measurements at 90 min, 6 h, 4 and 11 days following QUIN administration revealed highly elevated levels of the metabolite in the injected nuclei, with peak increases occurring after 4 days. Serotonin levels remained largely unchanged over the same time period. Direct visualization of hippocampal serotonergic fibers by immunohistochemistry demonstrated morphological changes (varicosities, swellings) in otherwise undamaged serotonin-positive afferents 4 days following a local QUIN injection. Hippocampal serotonin turnover was assessed at 4 days after an intrahippocampal QUIN-application: following inhibition of aromatic amino acid decarboxylase, the accumulation of 5-hydroxytryptophan was twice as rapid in QUIN-lesioned hippocampi as in controls. Dose-response relationships, examination of brain regions distant from the two injection sites and the temporal sequence of the changes described here suggest a close association between QUIN-induced neuronal degeneration and alterations in the serotonergic system.

Animals↗
PubMed1989

The quinolinic acid model of Huntington's disease: locomotor abnormalities.

In contrast to other excitotoxins, such as kainic acid, quinolinic acid (QA) may spare a specific population of striatal neurons that is also spared in Huntington's disease (HD). Although several histological and biochemical experiments support the use of QA as a model for HD, to date no behavioral experiments have been performed to examine the suitability of this model. The present study explored the behavioral effects of bilateral intrastriatal microinjections of four doses (75, 150, 225, 300 nmol) of QA in the male rat. Using a multidimensional analysis of spontaneous locomotion (Digiscan activity) and a record of metabolic indicators, such as weight loss, a dose-dependent effect was found. The 75-nmol dose had no significant effect on locomotion or feeding behavior. In contrast, the 150- and 225-nmol doses induced hyperactivity and weight loss, whereas the 300-nmol dose was lethal. The results obtained suggest that striatal injections of 150-225 nmol of QA induce behavioral deficits qualitatively similar though quantitatively less than those which are seen after similar injection of 3 nmol of kainic acid and which have been reported to be comparable to the symptomatology of HD. Together with QA's possible greater histological selectivity, the present results support the use of QA-induced striatal lesions as a behavioral model of Huntington's disease.

Animals↗
PubMed1990

Kynurenic acid antagonizes hippocampal quinolinic acid neurotoxicity: behavioral and histological evaluation.

In the present study, we evaluate the ability of kynurenic acid to protect hippocampal neurons from the neurotoxicity of the N-methyl-D-aspartate (NMDA) agonist quinolinic acid. Bilateral intrahippocampal injection of quinolinic acid (120 nmol) led to severe behavioral disturbances and total loss of hippocampal neurons. Intrahippocampal co-injection of kynurenic acid (360 nmol) completely prevented cell loss and behavioral disturbances. However, the protection was incomplete when kynurenic acid was intraperitoneally injected (500 mg/kg, repeated during 4 days). These above results indicate that kynurenic acid can antagonize the neuronal degeneration mediated by excessive stimulation of NMDA receptors in vivo.

Animals↗
PubMed1972

De novo biosynthesis of nicotinamide adenine dinucleotide in Escherichia coli: excretion of quinolinic acid by mutants lacking quinolinate phosphoribosyl transferase.

The excretion of quinolinic acid was studied in growing and resting cells of Escherichia coli K-12 nadC(13). Under optimal conditions, this organism could synthesize quinolinic acid in several-fold excess of the amount which would be required for normal growth. The excretion of quinolinic acid was controlled by the concentration of nicotinamide adenine dinucleotide (NAD) precursors available to the organism either during growth or during incubation in dense cell suspensions. These observations suggest that biosynthesis of NAD de novo is regulated by both repression and feedback inhibition. Analogues of niacin which inhibit bacterial growth also inhibited and repressed the synthesis (excretion) of quinolinic acid. The pH optimum for quinolinic acid excretion agreed favorably with the optimum observed for its synthesis in vitro. The rate of quinolinic acid excretion was strongly influenced by the concentration of ribose or glycerol in the medium.

Amino Acids↗