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PubMed1991

Is quinolinic acid an endogenous excitotoxin in alcohol withdrawal?

Levels of tryptophan in brain are increased by the action of chronic ethanol, particularly in the event of compromised hepatic function. This is likely to result in elevated brain levels of the potent excitotoxin quinolinic acid (quinolinate) since levels of this tryptophan metabolite can be elevated considerably by tryptophan loading. Ethanol may also selectively increase the activity of enzymes important in the synthesis of quinolinic acid such as tryptophan oxygenase. It is concluded that ethanol may generate significant levels of the NMDA receptor agonist, quinolinic acid, possibly even toxic levels in localized brain areas, especially during ethanol withdrawal and when associated with acute or chronic hepatotoxicity.

Alcoholism↗
PubMedDate not supplied

[Behavioral and EEG signs of the convulsive action of kynurenine and quinolinic acid in cats].

Administration of quinolinic acid but not L-kynurenine into the cat caudate nucleus was found to produce the appearance of epileptiform charges in the EEG with concomitant behavioral convulsions. A combination of quinolinic acid injections with systemic administration of penicillin resulted in the development of the status of myoclonic convulsions alternating with generalized tonicoclonic seizures. These states were eliminated by diazepam. The right caudate nucleus was revealed to be more sensitive as compared to the left one to the convulsant action of combined administration of quinolinic acid with penicillin.

Animals↗
PubMed1995

The relationship between plasma and brain quinolinic acid levels and the severity of hepatic encephalopathy.

BACKGROUND/AIMS: Quinolinic acid is an endogenous neuroexcitant derived from tryptophan. Brain quinolinic acid concentrations are reportedly elevated in chronic liver failure. The aim of this study was to determine if brain quinolinic acid levels correlate with the severity of hepatic encephalopathy. METHODS: Postmortem samples of selected brain regions and plasma samples taken at several stages of encephalopathy were obtained from patients with acute and chronic liver failure. Quinolinic acid levels were measured by mass spectroscopy using [18O]quinolinic acid. RESULTS: Plasma quinolinic acid levels were significantly increased by stage I encephalopathy in patients with acute liver failure and by stages II and III in patients with chronic liver failure. Brain quinolinic acid levels were elevated only in patients with acute liver failure and were uniformly distributed at concentrations below those observed in plasma. CONCLUSIONS: The uniform distribution of quinolinic acid at subplasma concentrations in the brains of patients with acute liver failure suggests that it is synthesized peripherally and enters the brain across a permeabilized blood-brain barrier. Whereas the elevation of brain quinolinic acid levels in patients who died of acute but not chronic liver failure suggests that the involvement of quinolinic acid in the pathogenesis of hepatic encephalopathy is minimal, it could predispose these patients to seizures.

Acute Disease↗
PubMed1985

Purification of quinolinic acid phosphoribosyltransferase from rat liver and brain.

Quinolinic acid phosphoribosyltransferase (EC 2.4.2.19) was purified 3600-fold from rat liver and 280-fold from rat brain. Kinetic analyses (Km = 12 microM for the substrate quinolinic acid and Km = 23 microM for the cosubstrate phosphoribosylpyrophosphate), physicochemical properties of the purified enzymes, inhibition by phthalic acid (Ki = 1.4 microM) and molecular weight determination (Mr 160 000 for the holoenzyme, consisting of five identical 32 kDa subunits) indicated the structural identity of quinolinic acid phosphoribosyltransferase from the two rat tissues. This was further confirmed immunologically, using antibodies raised against purified rat liver quinolinic acid phosphoribosyltransferase. Rat quinolinic acid phosphoribosyltransferase differs in several aspects from quinolinic acid phosphoribosyltransferase isolated from other organisms. The purified enzyme will prove a useful tool in the examination of a possible role of quinolinic acid in cellular function and/or dysfunction.

Animals↗
PubMed1994

Antibodies to quinolinic acid and the determination of its cellular distribution within the rat immune system.

Antibodies to quinolinic acid were produced in rabbits with protein-conjugated and gold particle-adsorbed quinolinic acid. Quinolinic acid immunoreactivity was below detection limits in carbodiimide-fixed rat brain. In contrast, strong quinolinic acid immunoreactivity was observed in spleen cells with variable, complex morphology located predominantly in the periarterial lymphocyte sheaths. In the thymus, quinolinic acid immunoreactivity was observed in cells with variable morphology, located almost exclusively in the medulla. Lymph nodes and gut-associated lymphoid tissue contained many, strongly stained cells of similar complex morphology in perifollicular areas. Immunoreactivity in liver and lung was restricted to widely scattered, perivascular cells and alveolar cells respectively. Additional stained cells with complex morphology were observed in bronchus-associated lymphoid tissue, in skin, and in the lamina propria of intestinal villi. Follicles in all secondary lymphoid organs were diffusely stained, ranging from mildly to moderately immunoreactive in spleen, to intensely immunoreactive in gut-associated lymphoid tissue. These results suggest that quinolinic acid is an immune system-specific molecule. Two hypothetical schemes are proposed to account for high levels of quinolinic acid in specific cells of the immune system.

Animals↗
PubMed2003

ECNI GC-MS analysis of picolinic and quinolinic acids and their amides in human plasma, CSF, and brain tissue.

To study the complex inter-relationships between inflammatory and apoptotic responses and the kynurenine pathway, we have utilized electron-capture negative ion mass spectrometry to develop trace analyses to concurrently quantify nicotinic acid (NIC), picolinic acid (PIC) and quinolinic acid (QUIN) in biological samples. We have shown that NIC and its amide nicotinamide (NAM) can be separately quantified by analyzing samples pre- and post-acid hydrolysis. We have now examined human plasma, CSF and brain tissue samples for the presence of putative picolinamide (PAM) and quinolinamide (QAM) by comparing PIC and QUIN concentrations pre- and post- gas phase hydrolysis. We report for the first time that, with respect to the free acids, relatively high concentrations of the amides (or, at least, hydrolysable precursors of the acids) are present in plasma and brain with marked relative increases in CSF. In normal control subjects (n=22) pre-hydrolysis plasma levels (+/- sem) of PIC and QUIN were 0.299 +/- 0.034 and 0.47 +/- 0.047 micromol/L respectively. Following hydrolysis the concentrations rose more than 4-fold to 1.33 +/- 0.115 and 2.2 +/- 0.27 micromol/L respectively. In CSF samples from patients with no sign of brain injury or pathology (n=10) pre-hydrolysis concentrations of PIC and QUIN were 0.017 +/- 0.005 and 0.018 +/- 0.006 micromol/L, respectively, which rose to 0.30 +/- 0.06 and 0.06 +/- 0.008 micromol/L respectively, after hydrolysis. In CSF samples from patients with a range of brain oedema or injury (eg subdural haemorrage, motor vehicle accident) (n=6) pre-hydrolysis concentrations of PIC and QUIN were 0.053 +/- 0.03 and 0.29 +/- 0.12 micromol/L, respectively. Following hydrolysis the concentrations were markedly increased to 6.06 +/- 1.5 and 0.94 +/- 0.63 micromol/L, respectively. The present investigation has shown for the first time that PAM and QAM are present endogenously with PAM being relatively higher than QAM, especially in CSF samples from patients with presumed brain inflammation. The site and mechanism of amidation of PIC and QUIN needs investigation.

Adult↗
PubMed1998

Role of zinc in blockade of excitotoxic action of quinolinic acid by picolinic acid.

This study examined whether picolinic acid (PIC) inhibits quinolinic acid (QUIN)-induced excitotoxicity through zinc chelation. Injection of QUIN into the nucleus basalis magnocellularis significantly depleted cortical choline acetyltransferase activity 7 days post injection and PIC inhibited this response. Zinc augmented the QUIN- but not NMDA-induced response. When PIC was co-administered with zinc, PIC failed to attenuate the QUIN-induced response. The inhibition of QUIN-induced cholinergic toxicity by PIC may involve chelation of zinc.

Animals↗
PubMed1988

Differential sensitivity of neuropeptide Y, somatostatin and NADPH-diaphorase containing neurons in rat cortex and striatum to quinolinic acid.

The tryptophan metabolite quinolinic acid (QUIN) was injected unilaterally into rat cerebral cortex or striatum in order to determine whether the neurotoxin would destroy neuropeptide Y (NPY)- and somatostatin (SS)-immunoreactive, and NADPH-diaphorase (NADPH-D)-containing neurons. Following intrastriatal injections of QUIN, NPY and SS immunoreactivity and NADPH-D-activity was absent in the injection core area. In contrast, cortical NPY- and SS-immunoreactive cells and NADPH-D-containing neurons were resistant to QUIN's neurotoxicity. These results suggest that in contrast to striatal neurons, cortical SS- and NPY-containing neurons do not express N-methyl-D-aspartate receptors.

Animals↗
PubMedDate not supplied

[Disorders in the behavioral development of rats in ontogeny after a single administration of quinolinic acid].

Repetitive administration of quinolinic acid (QUIN, 50 mg/kg) induced generalized seizures only in 11-12, but not in 2-3, or 5-6 day rat puppies. Behavioural patterns characterizing postnatal development were registered within 3 months. Hyperactivity, increased thresholds for nociceptive reaction, as well as a the impairment of memory and learning were found in rats treated with QUIN at the age of 5-6 days. Disturbances in postnatal development are presumably due to the sensitivity of the brain tissue to QUIN and to the critical period of development of the central nervous system. It is suggested that the syndrome of minimal brain disfunction may be related to accumulation of QUIN at critical periods in the development of the nervous system.

Aging↗
PubMedDate not supplied

Senile dementia and Alzheimer's disease: lack of changes of the cortical content of quinolinic acid.

The content of Quinolinic Acid (QUIN) was fragmentographically measured in the frontal, parietal and temporal cortex obtained at autopsy from patients affected by Alzheimer's disease-senile dementia Alzheimer type (AD/SDAT) or matched controls. The density of large cholinergic neurons in the nucleus basalis magnocellularis and the density of plaques in the hippocampal formation, parietal and frontal cortex of these patients was also evaluated in order to obtain a quantitative estimation of the Alzheimer type changes. In the three cortical areas studied, the content of QUIN was similar in AD/SDAT patients and age matched controls. The AD/SDAT patients had an important reduction of the number of large cholinergic neurons in the nucleus basalis magnocellularis and a much higher density of plaques in cortex and in hippocampus than age matched controls. The data reported here do not support the possibility than an accumulation of QUIN plays a role in the neuronal degeneration occurring in the cortex of patients affected by AD/SDAT.

Aged↗
PubMed1991

Immunohistochemical localization of quinolinic acid phosphoribosyltransferase in the human neostriatum.

The localization and distribution of quinolinic acid phosphoribosyltransferase, the degradative enzyme of the endogenous excitotoxin quinolinic acid, were studied in the post mortem human neostriatum by immunohistochemistry. In eight neurologically normal human brains, quinolinic acid phosphoribosyltransferase immunoreactivity was detected in both glial cells and neurons. Typically, glial cells containing quinolinic acid phosphoribosyltransferase immunoreactivity had numerous processes radiating from the cell bodies. In Nissl-counterstained sections, most quinolinic acid phosphoribosyltransferase-immunoreactive glial cells showed round, large and pale nuclei. These morphological features indicate that they are probably astrocytes. Neurons containing quinolinic acid phosphoribosyltransferase immunoreactivity had different sizes and shapes and were tentatively classified into three subpopulations. Most were medium-sized cells with ovoid or elongated perikarya. Small quinolinic acid phosphoribosyltransferase-immunoreactive neurons, often spheroid in shape, were particularly noted in a zone of the caudate nucleus adjacent to the lateral ventricle. A few large quinolinic acid phosphoribosyltransferase-positive neurons were also present in both the caudate and putamen. The somatic and dendritic morphology of quinolinic acid phosphoribosyltransferase-immunoreactive neurons closely resembles that of aspiny neurons seen in Golgi preparations. The localization of the specific quinolinic acid-catabolizing enzyme in distinct populations of neostriatal cells suggests specific functional correlates. It remains to be examined how the anatomical organization of quinolinic acid phosphoribosyltransferase immunoreactivity relates to the degradation of quinolinic acid in the striatum, and if the morphological characteristics and distribution of quinolinic acid phosphoribosyltransferase-immunoreactive cells are of relevance for the pathogenesis of neurodegenerative basal ganglia disorders.

Adult↗
PubMed1992

Poliovirus induces indoleamine-2,3-dioxygenase and quinolinic acid synthesis in macaque brain.

Accumulation of the neurotoxin quinolinic acid within the brain occurs in a broad spectrum of patients with inflammatory neurologic disease and may be of neuropathologic significance. The production of quinolinic acid was postulated to reflect local induction of indoleamine 2,3-dioxygenase by cytokines in reactive cells and inflammatory cell infiltrates within the central nervous system. To test this hypothesis, macaques received an intraspinal injection of poliovirus as a model of localized inflammatory neurologic disease. Seventeen days later, spinal cord indoleamine 2,3-dioxygenase activity and quinolinic acid concentrations in spinal cord and cerebrospinal fluid were both increased in proportion to the degree of inflammatory responses and neurologic damage in the spinal cord, as well as the severity of motor paralysis. The absolute concentrations of quinolinic acid achieved in spinal cord and cerebrospinal fluid exceeded levels reported to kill spinal cord neurons in vitro. Smaller increases in indoleamine 2,3-dioxygenase activity and quinolinic acid concentrations also occurred in parietal cortex, a poliovirus target area. In frontal cortex, which is not a target for poliovirus, indoleamine 2,3-dioxygenase was not affected. A monoclonal antibody to human indoleamine 2,3-dioxygenase was used to visualize indoleamine 2,3-dioxygenase predominantly in grey matter of poliovirus-infected spinal cord, in conjunction with local inflammatory lesions. Macrophage/monocytes in vitro synthesized [13C6]quinolinic acid from [13C6]L-tryptophan, particularly when stimulated by interferon-gamma. Spinal cord slices from poliovirus-inoculated macaques in vitro also converted [13C6]L-tryptophan to [13C6]quinolinic acid. We conclude that local synthesis of quinolinic acid from L-tryptophan within the central nervous system follows the induction of indoleamine-2,3-dioxygenase, particularly within macrophage/microglia. In view of this link between immune stimulation and the synthesis of neurotoxic amounts of quinolinic acid, we propose that attenuation of local inflammation, strategies to reduce the synthesis of neuroactive kynurenine pathway metabolites, or drugs that interfere with the neurotoxicity of quinolinic acid offer new approaches to therapy in inflammatory neurologic disease.

Animals↗
PubMed1991

Neurotoxicity of quinolinic acid and its derivatives in hypoxic rat hippocampal slices.

The excitotoxicity of quinolinic acid (2,3-pyridinedicarboxylic acid), a potent endogenous N-methyl-D-aspartate (NMDA)-type agonist, was characterized in the hypoxic hippocampal slice preparation. A series of other pyridinedicarboxylic acids was also tested in this preparation in order to obtain information about the structural requirements for the interaction between the NMDA receptor and its agonists. Of the 7 pyridinedicarboxylic acids tested, only quinolinic acid and its anhydride exerted their excitotoxicity by enhancing hypoxic neuronal damage in rat hippocampal slices at a relatively low concentration (100 microM). Much higher concentration (1 mM) of 3,4-pyridinedicarboxylic acid was required to exhibit any enhancement of hypoxic neuronal damage. The rest of the derivatives were innocuous. The effect of quinolinic acid was blocked by DL-2-amino-5-phosphonovaleric acid, by elevated magnesium levels in the incubation medium or by perfusion with a medium depleted of calcium. Aglycemic damage was also enhanced by quinolinic acid. It appears from the present study that two adjacent carboxylic groups on the pyridine ring, preferably at positions 2 and 3, are a prerequisite for an interaction between the NMDA receptor and its agonist. However, other factors may have great influence on that interaction as was evident from the total impotency of 6-methyl-quinolinic acid. The hypoxic hippocampal slice preparation and its neuronal function is an inexpensive model system, sensitized to the neurotoxins, and thus, allows the easy screening and evaluation of potential ligands of the glutamate receptor and its subtypes.

2-Amino-5-phosphonovalerate↗
PubMed1985

In vivo brain dialysis of amino acids and simultaneous EEG measurements following intrahippocampal quinolinic acid injection: evidence for a dissociation between neurochemical changes and seizures.

The extracellular content of taurine, glutamate, glutamine, and glycine was measured by the novel method of brain dialysis in the acute phases following an intrahippocampal injection of the excitotoxic convulsant brain metabolite quinolinic acid (QUIN). Using bilaterally implanted depth electrodes physically combined with hollow fibers for dialysis, it was possible to collect continuously brain perfusates while simultaneously monitoring brain activity in the unanesthetized rat. In separate animals, hippocampal amino acid tissue levels were measured 2 h after an intracerebral injection of a convulsant dose (156 nmol) of QUIN. When compared with those in animals receiving the nonconvulsant decarboxylation product of QUIN, nicotinic acid, no differences in tissue levels were detected. In contrast, the same dose of QUIN caused a selective increase (2.24-fold) in taurine levels in perfusates from the injected hippocampus. These changes were apparent prior to the onset of electrographic seizures and did not occur in the contralateral hippocampus where seizure activity was equally severe. Thus, increases in extracellular taurine, triggered by the presence of QUIN in the hippocampus, may reflect a selective tissue response to the neurotoxic (rather than the convulsant) effects of this excitotoxin.

Amino Acids↗
PubMed1994

Picolinic acid blocks the neurotoxic but not the neuroexcitant properties of quinolinic acid in the rat brain: evidence from turning behaviour and tyrosine hydroxylase immunohistochemistry.

Previous results suggest that the tryptophan metabolite, picolinic acid may have the unusual properties of antagonizing the neurotoxic but not the neuroexcitant effects of another tryptophan metabolite, quinolinic acid in the central nervous system. The present experiments tested this possibility utilizing behavioural and tyrosine hydroxylase immunohistochemical techniques. In the first series of experiments, rats received injections of relatively high concentrations of 6-hydroxydopamine (12 micrograms in 1 or 2 microliters), quinolinic acid (120 nmol in 0.5 microliters), picolinic acid (480 nmol in 0.5 microliters) or co-treatments (0.5 microliters) with quinolinic (120 nmol) plus picolinic acid (480 nmol) into the region of the substantia nigra. Results revealed that 6-hydroxydopamine and quinolinic acid alone produced a large loss of tyrosine hydroxylase-positive cells in the pars compacta of the substantia nigra. Behavioural results for all 6-hydroxydopamine (n = 10) and for some quinolinate-treated rats (n = 5) revealed ipsi- and contraversive circling following amphetamine (1 mg/kg, i.p.) and apomorphine (0.5 mg/kg, s.c.), respectively, consistent with unilateral loss of dopamine cells in the substantia nigra. The remaining quinolinate-treated rats (n = 9) circled ipsiversively following either stimulant suggesting damage to the pars reticulata. Groups treated with picolinic acid alone (n = 6) or co-injected (n = 6) showed no loss of tyrosine hydroxylase-positive cells in the substantia nigra and no circling response to the stimulants. In the second series of experiments, low concentrations of quinolinic acid (2.5, 5.0, 7.5 nmol), picolinic acid (10, 20, 30 nmol), or the two together (7.5 plus 30 nmol, respectively) were microinjected (0.5 microliter) into the dorsal striatum and circling behaviour evaluated. These results revealed dose-dependent contralateral circling with either quinolinate or picolinate; co-injection of the two tryptophan metabolites also produced contralateral circling. It was concluded that picolinic acid blocks the neurotoxic but not the neuroexcitant effects of quinolinic acid.

Animals↗
PubMed1984

Excitant activity of methyl derivatives of quinolinic acid on rat cortical neurones.

Various synthetic analogues of quinolinic acid have been tested for agonist and antagonist properties when applied by microiontophoresis to neurones in the rat cerebral cortex. Quinolinic acid 2-methylester was a weak antagonist of N-methyl-D-aspartate (NMDA) and quinolinic acid, but also showed agonist activity, being about half as active as quinolinic acid. The excitant effects of the compound could be antagonized by the NMDA receptor blocker, 2-amino-7-phosphonoheptanoic acid (2APH). N-methyl-quinolinic acid 2, 3-dimethylester showed very weak agonist and antagonist activity. Homoquinolinic acid was a potent excitant of cortical neurones, being about five times more active than quinolinic acid and approximately equipotent with NMDA. The excitations were blocked by 2APH or its pentanoate analogue (2APV). Homoquinolinic acid 2-methylester was also active as an agonist. N-methyl-DL-glutamic acid was also tested, since homoquinolinic acid is a rigid analogue of this compound. Although it did cause excitation of 5 of the 16 units tested, N-methyl-glutamate was a weaker agonist than NMDA or homoquinolinate. Phthalic acid, ejected as an anion caused excitation of 14 out of 16 units. It is therefore concluded that the ring nitrogen of quinolinic acid is not essential for excitant activity. Since homoquinolinic acid is a rigid analogue of glutamic acid, but causes excitation by acting apparently on the NMDA receptor, the results are consistent with the suggestion that activation of the NMDA receptor may require the carboxyl groups to be held in a relatively extended configuration.

Animals↗
PubMed2003

Regioselective hydroxylation of quinolinic acid, lutidinic acid and isocinchomeronic acid by resting cells of pyridine dicarboxylic acid-degrading microorganisms.

Microorganisms aerobically degrading quinolinic acid, lutidinic acid or isocinchomeronic acid were isolated and the microbial regioselective hydroxylation of these pyridine dicarboxylic acids was studied. Alcaligenes sp. UK21 cells converted quinolinic acid into 6-hydroxypicolinic acid, suggesting the involvement of two enzyme reactions catalyzing hydroxylation at position C6 and decarboxylation at position C3 of quinolinic acid. Resting cells of Alcaligenes sp. UK21 accumulated 94.9 mM 6-hydroxypicolinic acid (13.2 g l(-1)), with a 96% molar conversion yield by 48 h incubation. Rhizobium sp. LA17 and Hydrogenophaga sp. IMA01 catalyzed the regioselective hydroxylation of lutidinic acid and isocinchomeronic acid into 6-hydroxylutidinic acid and 6-hydroxyisocinchomeronic acid, respectively. 6-Hydroxylutidinic acid accumulated up to 95.4 mM (17.5 g l(-1)) by 24 h incubation in the resting cells reaction, using Rhizobium sp. LA17, with a 99% molar conversion yield. Resting cells of Hydrogenophaga sp. IMA01 produced 88.7 mM 6-hydroxyisocinchomeronic acid (16.2 g l(-1)) by 24 h incubation, with a 81% molar conversion yield.

Alcaligenes↗