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PubMed1999

Quinolinic acid is extruded from the brain by a probenecid-sensitive carrier system: a quantitative analysis.

Although the neurotoxic tryptophan-kynurenine pathway metabolite quinolinic acid originates in brain by both local de novo synthesis and entry from blood, its concentrations in brain parenchyma, extracellular fluid, and CSF are normally below blood values. In the present study, an intraperitoneal injection of probenecid (400 mg/kg), an established inhibitor of acid metabolite transport in brain, into gerbils, increased quinolinic acid concentrations in striatal homogenates, CSF, serum, and homogenates of kidney and liver. Direct administration of probenecid (10 mM) into the brain compartment via an in vivo microdialysis probe implanted into the striatum also caused a progressive elevation in both quinolinic acid and homovanillic acid concentrations in the extracellular fluid compartment but was without effect on serum quinolinic acid levels. A model of microdialysis transport showed that the elevations in extracellular fluid quinolinic acid and homovanillic acid levels following intrastriatal application are consistent with probenecid block of a microvascular acid transport mechanism. We conclude that quinolinic acid in brain is maintained at concentrations below blood levels largely by active extrusion via a probenecid-sensitive carrier system.

Animals↗
PubMed1990

Increased cerebrospinal fluid quinolinic acid, kynurenic acid, and L-kynurenine in acute septicemia.

Increases in brain quinolinic acid have been implicated in neurodegeneration and convulsions that may accompany infectious diseases. In three rhesus macaques (Macaca mulatta) with septicemia, both CSF and serum quinolinic acid concentrations were markedly elevated and were accompanied by increases in CSF kynurenic acid levels that were of a smaller magnitude. Elevated serum and CSF L-kynurenine concentrations also occurred and are consistent with activation of indoleamine-2,3-dioxygenase and increased substrate flux through the kynurenine pathway. Although it is probable that the marked increases in CSF quinolinic acid and kynurenic acid concentrations are reflected in the extracellular fluid space of brain, it remains to be determined whether the magnitude of such increases influences the activity of excitatory amino acid receptors in brain to produce excitotoxic pathology or noncytolytic disruption of functions mediated by excitatory amino acid receptors.

Acute Disease↗
PubMed1990

Extracellular levels of quinolinic acid are moderately increased in rat neostriatum following severe insulin-induced hypoglycaemia.

Extracellular concentrations of the brain metabolite quinolinic acid, an endogenous excitotoxin, were monitored by microdialysis in rat neostriatum and hippocampus/cortex during and following a 30-min period of insulin-induced hypoglycaemia. During hypoglycaemia-induced isoelectricity, extracellular levels of quinolinic acid in the striatum (basal value, 1.1 +/- 0.3 pmol per 30-microliters fraction) were elevated 1.7 times as compared to the control period. Thirty to ninety minutes following hypoglycaemia a significant increase in extracellular quinolinic acid to 2.2 times basal level was noted. After 2 h recovery, the beginning of neuronal necrosis was observed in the dorsolateral striatum. Implantation of the dialysis probe did not influence the extent of neuronal damage. No changes in extracellular quinolinic acid levels were observed in the hippocampus/cortex. The data indicate that following a severe hypoglycaemic insult vulnerable striatal cells are exposed to hyperphysiological extracellular quinolinic acid concentrations over an extended period of time. Considering the pronounced susceptibility of rat striatal neurons to the toxin, the small but prolonged elevation in the extracellular levels of quinolinic acid could be of significance for the development of delayed neuronal death in hypoglycaemia.

Animals↗
PubMed1996

Quinolinic acid in patients with systemic lupus erythematosus and neuropsychiatric manifestations.

OBJECTIVE: To evaluate the relationship between quinolinic acid, a neuroactive metabolite of L-tryptophan, and neuropsychiatric manifestations of systemic lupus erythematosus (SLE). METHODS: Forty specimens of cerebrospinal fluid (CSF) were obtained from 39 patients with SLE who were evaluated for 40 episodes of neuropsychiatric dysfunction. The diagnosis of the neuropsychiatric dysfunction was determined clinically. CSF and serum specimens were analyzed for levels of quinolinic acid without knowledge of the clinical diagnosis. RESULTS: Neuropsychiatric dysfunction attributed to SLE (NPSLE) was confirmed in 30 patient-episodes (Group 1), whereas in the other 10 (Group 2) other etiologies were felt to explain their CNS dysfunction. The median levels of CSF quinolinic acid for Group 1 (232.5 nmol/l) were significantly higher than those for Group 2 (median 38.2 nmol/l) (p < 0.014). CSF and serum quinolinic acid levels correlated significantly (p < 0.003) but there was not correlation between CSF quinolinic acid and CSF protein concentrations or white blood cell counts. CONCLUSION: We conclude that elevated quinolinic acid levels in the CSF and serum may be associated with NPSLE and could possibly play a role in its pathogenesis.

Adult↗
PubMed1986

A radioenzymatic assay for quinolinic acid.

A new and rapid method for the determination of the excitotoxic tryptophan metabolite quinolinic acid is based on its enzymatic conversion to nicotinic acid mononucleotide and, in a second step utilizing [3H]ATP, further to [3H] deamido-NAD. Specificity of the assay is assured by using a highly purified preparation of the specific quinolinic acid-catabolizing enzyme, quinolinic acid phosphoribosyltransferase, in the initial step. The limit of sensitivity was found to be 2.5 pmol of quinolinic acid, sufficient to conveniently determine quinolinic acid levels in small volumes of human urine and blood plasma.

Adult↗
PubMed2003

Dietary linoleic acid suppresses gene expression of rat liver alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) and increases quinolinic acid in serum.

Hepatic ACMSD [EC4.1.1.45] plays a key role in regulating NAD biosynthesis from tryptophan. We previously reported that ingestion of polyunsaturated fatty acids by rats leads to a decrease in their hepatic ACMSD activity. We purified ACMSD and cloned cDNA encoding rat ACMSD. Therefore, in this study, we examined whether dietary linoleic acid altered ACMSD gene expression and its protein level. Moreover we measured the tryptophan catabolite quinolinic acid level in rats. In the rats fed with linoleic acid, ACMSD mRNA and its protein levels in the liver were strongly suppressed and serum quinolinic acid was significantly increased as compared with the rats fed on a fat-free diet. These results suggest that the transcription level of ACMSD is modulated by linoleic acids or their metabolites and probably there is an inverse relationship between ACMSD activity and the production of quinolinic acid converted from tryptophan.

Animals↗
PubMed1991

Quinolinic acid catabolism is increased in cerebellum of patients with dominantly inherited olivopontocerebellar atrophy.

We measured the activities of the enzymes responsible for the metabolism of the excitotoxin quinolinic acid, 3-hydroxyanthranilate oxygenase and quinolinic acid phosphoribosyltransferase, in autopsied brain of 11 patients with olivopontocerebellar atrophy. In cerebellar cortex, severe Purkinje cell loss was evident but with relative preservation of granule cells. As compared with the control subjects (n = 14), mean activity of 3-hydroxyanthranilate oxygenase was normal in cerebellar cortex from the patients with olivopontocerebellar atrophy, whereas quinolinic acid phosphoribosyltransferase activity was markedly increased (+92%, p less than 0.02). No significant changes in enzyme activities were found in samples from occipital cortex. Increased quinolinic acid phosphoribosyltransferase activity may represent a mechanism, in the degenerating cerebellum, to protect quinolinic acid-sensitive granule cells in patients with olivopontocerebellar atrophy.

Adult↗
PubMed1986

Neuropharmacological actions of kynurenic and quinolinic acids on horizontal cells of the isolated fish retina.

We have studied the effects of naturally occurring metabolites of tryptophan, kynurenic and quinolinic acids, on the electrophysiological responses of retinal horizontal cells in the fish (Rutilus rutilus, the roach). Quinolinic acid usually hyperpolarizes the cells and reduces their light evoked responses (S-potentials) but on occasion, it causes a slight depolarization of the membrane potential. These actions are similar to those found with N-methyl-D-aspartate (NMDA) and our results are consistent with the proposal that it acts at NMDA binding sites. Kynurenic acid (greater than or equal to mM) invariably hyperpolarizes horizontal cells to their potassium Nernst equilibrium potential and, more significantly, blocks the depolarizing actions exerted on them by excitatory amino acids, such as kainic and quisqualic acids. We show that this action persists in the presence of the synaptic blocker, cobalt chloride, and thus is not mediated by chemical synaptic activity. Kynurenic acid does not reverse depolarization of horizontal cells by dopamine or gamma-aminobutyric acid, thus its inhibitory effects are selective to the actions of excitatory amino acids. Neither xanthurenic acid, a close structural analogue of kynurenic acid, nor quinolinic acid are effective in blocking depolarizations by excitatory amino acids.

Animals↗
PubMed1991

Prolonged infusion of quinolinic acid into rat striatum as an excitotoxic model of neurodegenerative disease.

The neurotoxic effects of prolonged exposure of rat striatum to quinolinic acid in vivo was evaluated through assays of neurochemical markers for major neuronal populations. Continuous intrastriatal quinolinic acid infusion for 14 days produced a dose-dependent depletion of striatal choline acetyltransferase (ChAT) activity, glutamic acid decarboxylase (GAD) activity, and somatostatin content. ChAT activity was significantly reduced by quinolinic acid at doses of 90, 270, and 540 nmol/day, while GAD activity and somatostatin content were decreased only at doses of 270 and 540 nmol/day. NADPH-diaphorase histochemistry revealed a loss of striatal NADPH-diaphorase neurons as a result of quinolinic acid infusion at a dose of 270 nmol/day. The neurotoxic lesion induced by prolonged quinolinic acid exposure in vivo can be used as a potential model for studying excitotoxic mechanisms in neurodegenerative disease.

Animals↗
PubMed1989

Neuroactive metabolites of L-tryptophan, serotonin and quinolinic acid, in striatal extracellular fluid. Effect of tryptophan loading.

Extracellular fluid levels of the neurotoxin quinolinic acid in the corpus striatum of rats, measured by in vivo microdialysis, were increased in a dose-dependent manner following the intraperitoneal administration of tryptophan. The lowest dose of tryptophan (12.5 mg/kg), equivalent to about 5% of the normal daily intake, increased peak quinolinic acid levels nearly 3-fold. At higher doses of tryptophan (up to 250 mg/kg), concentrations of quinolinic acid increased over 200-fold and exceeded potentially neurotoxic levels (10 microM). In contrast, the increase in extracellular serotonin following even the highest tryptophan dose was small (less than 2-fold). These data indicate that quinolinic acid is present in the extracellular fluid where it may function as a neuromodulator and that it is very responsive to physiological changes in precursor availability.

Animals↗
PubMed1990

[The neurodegenerative and convulsant action of quinolinic acid].

Convulsant and neurodestructive action of intraventricular administration of quinolinic acid was studied in rats. It was found that severity of neurodegenerative changes in the hippocamp depended on the dose of that metabolite and correlated but slightly with the intensity of seizures. Destructions induced by quinolinic acid in the CNS did not change seizures induced by subsequent injections of the compound.

Animals↗
PubMedDate not supplied

[Electroencephalographic manifestations of the convulsive reaction of rats to the intraventricular administration of quinolinic acid and kynurenine].

The EEG responses to intraventricular administration of quinolinic acid (1.5 and 10 mg), pentylenetetrazole (500 micrograms) and kynurenine (200 and 400 micrograms) were studied. Quinolinic acid was found to produce the convulsive discharges in the EEG 30-60 sec after administration. Similar results were obtained following administration of pentylenetetrazole, the first EEG disturbances being recorded in both cases in the leads from the caudate nucleus and hippocampus. Kynurenine administered intraventricularly failed to change the initial EEG in rats. The possible triggering role of the caudate nucleus in the mechanism of quinolinic acid-induced convulsions is suggested.

Animals↗
PubMed1998

Effects of electromagnetic fields on the levels of biogenic amine metabolites, quinolinic acid, and beta-endorphin in the cerebrospinal fluid of dairy cows.

Eight multiparous non-lactating pregnant Holstein cows at 198 +/- 35 d of gestation, weighing 608 +/- 24 kg, were confined to wooden metabolic cages in an electric and magnetic field chamber with a 12:12 h light:dark cycle. Subarachnoidal catheters were installed 5 d before the activation of the electric and magnetic fields. The cows were exposed to electric and magnetic fields (60 Hz, 10 kV/m and 30 microT) continuously except for the feeding and cleaning time for an average of 21.44 +/- 1.4 h per day for a period of 30 d. Cerebrospinal fluid samples were collected on three consecutive days before an exposure period of 30 d, on the last 3 d of the exposure period, and for 3 d starting 5 d after the exposure period. The concentrations of beta-endorphin, tryptophan, 5-hydroxyindoleacetic acid, homovanillic acid, 3-methoxy-4-hydroxyphenylethyleneglycol and quinolinic acid in cerebrospinal fluid were determined. There was a significant increase in quinolinic acid, and a trend towards an increase in tryptophan, findings consistent with a weakening of the blood-brain barrier due to exposure to the electric and magnetic fields.

Animals↗
PubMed1995

Effect of quinolinic acid administration on rat liver: ultrastructural investigation.

Quinolinic acid was administered intraperitoneally in a dose of 30 or 60 mmol, once every 24 h for 8 days. Its result in the dose of 30 mmol was the proliferation of smooth elements of the endoplasmic reticulum. The use of quinolinic acid in a dose of 60 mmol was characterized by the presence of more profound damage of organelles, among them the distinct decrease of the rough elements of the endoplasmic reticulum and polyribosomal structures was seen, and moreover, wide areas devoid of organelles were observed.

Animals↗