[Quinolinic acid as a precursor of nicotinic acid].
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Niacin↗
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The anti-inflammatory effects of quinolinic acid in the rat.
Quinolinic acid (QUIN) levels are elevated in patients and animals suffering from chronic infectious diseases. In the present study, male Sprague-Dawley rats were used to test the anti-inflammatory effects of QUIN using the carrageenan (CGN)-induced paw edema assay and the CGN sponge assay. Results of these studies indicate that QUIN (30, 100 or 300 mg/kg i.p.) caused a reduction of carrageenan-induced inflammation by as much as 80% at the highest dose. Moreover, QUIN reduced exudate volume and inhibited leukocyte migration in the sponge granuloma assay. In another experiment, the anti-inflammatory activity of QUIN was eliminated in adrenalectomized rats. QUIN did not reduce edema caused by arachidonic acid, bradykinin or compound 48/80. Neither morphine nor naloxone altered the anti-inflammatory activity of QUIN. These results may suggest that QUIN exerts its anti-inflammatory activity through a direct action on neutrophils or vascular permeability.
Animals↗
Normal excretion of quinolinic acid in Huntington's disease.
We measured the excretion of the endogenous neurotoxin quinolinic acid in 14 patients with Huntington's disease and in 11 age matched control subjects. Huntingtonian patients excreted less quinolinic acid, than controls. When normalised to urea or creatinine output quinolinic acid excretion was normal. We conclude that Huntington's disease is not associated with a generalised disturbance of quinolinic acid metabolism, however, a local hyperproduction of quinolinic acid cannot be excluded from our results.
Adolescent↗
Quinolinic acid is increased in CSF and associated with mortality after traumatic brain injury in humans.
We tested the hypothesis that quinolinic acid, a tryptophan-derived N-methyl-D-aspartate agonist produced by macrophages and microglia, would be increased in CSF after severe traumatic brain injury (TBI) in humans, and that this increase would be associated with outcome. We also sought to determine whether therapeutic hypothermia reduced CSF quinolinic acid after injury. Samples of CSF (n = 230) were collected from ventricular catheters in 39 patients (16 to 73 years old) during the first week after TBI, (Glasgow Coma Scale [GCS] < 8). As part of an ongoing study, patients were randomized within 6 hours after injury to either hypothermia (32 degrees C) or normothermia (37 degrees C) treatments for 24 hours. Otherwise, patients received standard neurointensive care. Quinolinic acid was measured by mass spectrometry. Univariate and multivariate analyses were used to compare CSF quinolinic acid concentrations with age, gender, GCS, time after injury, mortality, and treatment (hypothermia versus normothermia). Quinolinic acid concentration in CSF increased maximally to 463 +/- 128 nmol/L (mean +/- SEM) at 72 to 83 hours after TBI. Normal values for quinolinic acid concentration in CSF are less than 50 nmol/L. Quinolinic acid concentration was increased 5- to 50-fold in many patients. There was a powerful association between time after TBI and increased quinolinic acid (P < 0.00001), and quinolinic acid was higher in patients who died than in survivors (P = 0.003). Age, gender, GCS, and treatment (32 degrees C versus 37 degrees C) did not correlate with CSF quinolinic acid. These data reveal a large increase in quinolinic acid concentration in CSF after TBI in humans and raise the possibility that this macrophage-derived excitotoxin may contribute to secondary damage.
Adolescent↗
Amino acid neurotransmitter abnormalities in Huntington's disease and the quinolinic acid animal model of Huntington's disease.
Concentrations of gamma-aminobutyric acid (GABA), glutamate, aspartate, and taurine were measured in postmortem tissue from the brains of patients with Huntington's disease (HD) and in the quinolinic acid (QA) lesioned rat striatum. The aim of the study was to assess further the ability of the QA model of HD to reproduce the neurochemical features of the disease. Nine cortical and 9 subcortical regions were examined from 17 pathologically graded cases of HD and 10 controls. Significant reductions in both GABA and glutamate were found in HD striatum. The reductions were greater in the more severely affected grades of HD, and there was a gradient of amino acid loss across the striatal nuclei (caudate greater than putamen greater than nucleus accumbens) which was consistent with the known pattern of pathological involvement. Taurine and aspartate concentrations showed no significant change. GABA reductions were found in both segments of the globus pallidus (external greater than internal) and both parts of the substantia nigra (reticulata greater than compacta). In advanced cases of HD, there were significant reductions in glutamate in Brodmann cortical areas 3-1-2, 6, 9, and 17, but GABA, aspartate, and taurine were unaltered in the cortex. The QA lesions reproduced the striatal deficits of both GABA and glutamate but, in contrast to HD, there was a decrease in taurine, possibly due to species differences. Chronic QA lesions resulted in a secondary dying back of corticostriatal glutamatergic terminals, but did not produce a change in cortical glutamate concentration. This suggests that reductions in cortical glutamate in HD may reflect a primary loss of glutamatergic neurons. Our findings extend previous observations on amino acid neurotransmitters in HD and, with the exception of taurine, confirm the general applicability of the QA model.
Amino Acids↗
Short- and long-term consequences of intracranial injections of the excitotoxin, quinolinic acid, as evidenced by GFA immunohistochemistry of astrocytes.
Astroglial reactions to intrastriatal and intrahypothalamic injections of the endogenous excitotoxin quinolinic acid (50 micrograms in 1 microliter) were studied in adult rats, using immunohistochemistry with antiserum to glial fibrillary acidic protein. Animals were sacrificed 6 h, 24 h, 3, 7 and 30 days or 1 year after the injection. Six and 24 h after quinolinic acid, the amount of glial fibrillary acidic protein-like immunoreactivity in the injected striatum was lower than in controls but returned to a normal level at 3 days. Not until 7 days was a clear striatal gliosis apparent, as evidenced by an increased density of glial fibrillary acidic protein-positive structures and brightly fluorescent, clearly hypertrophic cells. This gliosis was even more developed in animals sacrificed 30 days postoperatively. A weak astrocytic reaction was also observed in the ipsilateral corpus callosum at 6 h after quinolinic acid. By 3 days, a marked gliosis restricted to the injected hemisphere was present throughout corpus callosum and cortex cerebri. In animals sacrificed 30 days after quinolinic acid the extrastriatal astrocytic reaction was clearly diminished, although the striatal gliosis was still prominent. One year postinjection, no obvious gliosis could be observed in cortex cerebri or corpus callosum while striatal tissue, now markedly reduced in volume, was clearly gliotic. Using neurofilament antiserum, increased fluorescence intensity was noted in striatal nerve bundles during the first day after an intrastriatal quinolinic acid injection and persisted 1 year postoperatively. Controls were similarly injected with an equimolar amount of nicotinic acid, the non-excitatory, non-neurotoxic decarboxylation product of quinolinic acid. No changes in immunoreactivity of glial fibrillary acidic protein or neurofilament were found in these animals. In animals treated intrahypothalamically, a spherical central area almost devoid of glial fibrillary acidic protein-immunoreactivity was noted around the injection site 7 days after quinolinic acid administration. Around this area, gliosis was observed. Apart from a very restricted gliotic reaction around the needle tract, no astrocytic reaction was observed in nicotinic acid-injected control animals. We conclude that quinolinic acid causes both reversible and long-lasting gliosis when injected into the rat striatum. As a natural brain metabolite, quinolinic acid may constitute a particularly valuable tool for the elucidation of a possible role of glia in neurodegenerative disorders.
Animals↗
Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques.
This study investigated the sources of quinolinic acid, a neurotoxic tryptophan-kynurenine pathway metabolite, in the brain and blood of HIV-infected patients and retrovirus-infected macaques. In brain, quinolinic acid concentrations in HIV-infected patients were elevated by > 300-fold to concentrations that exceeded cerebrospinal fluid (CSF) by 8.9-fold. There were no significant correlations between elevated serum quinolinic acid levels with those in CSF and brain parenchyma. Because nonretrovirus-induced encephalitis confounds the interpretation of human postmortem data, rhesus macaques infected with retrovirus were used to examine the mechanisms of increased quinolinic acid accumulations and determine the relationships of quinolinic acid to encephalitits and systemic responses. The largest kynurenine pathway responses in brain were associated with encephalitis and were independent of systemic responses. CSF quinolinic acid levels were also elevated in all infected macaques, but particularly those with retrovirus-induced encephalitis. In contrast to the brain changes, there was no difference in any systemic measure between macaques with encephalitis vs. those without. Direct measures of the amount of quinolinic acid in brain derived from blood in a macaque with encephalitis showed that almost all quinolinic acid (>98%) was synthesized locally within the brain. These results demonstrate a role for induction of indoleamine-2,3dioxygenase in accelerating the local formation of quinolinic acid within the brain tissue, particularly in areas of encephalitis, rather than entry of quinolinic acid into the brain from the meninges or blood. Strategies to reduce QUIN production, targeted at intracerebral sites, are potential approaches to therapy.
Acquired Immunodeficiency Syndrome↗
Evidence that quinolinic acid severely impairs energy metabolism through activation of NMDA receptors in striatum from developing rats.
In the present study we investigated the effect of intrastriatal administration of 150 nmol quinolinic acid to young rats on critical enzyme activities of energy production and transfer, as well as on 14CO2 production from [1-14C]acetate at distinct periods after quinolinic acid injection. We observed that quinolinic acid injection significantly inhibited complexes II (50%), III (46%) and II-III (35%), as well as creatine kinase (27%), but not the activities of complexes I and IV and citrate synthase in striatum prepared 12 h after treatment. In contrast, no alterations of these enzyme activities were observed 3 or 6 h after quinolinic acid administration. 14CO2 production from [1-14C]acetate was also significantly inhibited (27%) by quinolinic acid in rat striatum prepared 12 h after injection. However, no alterations of these activities were observed in striatum homogenates incubated in the presence of 100 microm quinolinic acid . Pretreatment with the NMDA receptor antagonist MK-801 and with creatine totally prevented all inhibitory effects elicited by quinolinic acid administration. In addition, alpha-tocopherol plus ascorbate and the nitric oxide synthase inhibitor l-NAME completely abolished the inhibitions provoked by quinolinic acid on creatine kinase and complex III. Furthermore, pyruvate pretreatment totally blocked the inhibitory effects of quinolinic acid injection on complex II activity and partially prevented quinolinic acid-induced creatine kinase inhibition. These observations strongly indicate that oxidative phosphorylation, the citric acid cycle and cellular energy transfer are compromised by high concentrations of quinolinic acid in the striatum of young rats and that these inhibitory effects were probably mediated by NMDA stimulation.
Animals↗
Quinolinic acid: effects on brain catecholamine and c-AMP content during L-dopa and reserpine administration.
The catecholamine content in rat brain tissue was determined following the administration of quinolinic acid alone or combined either with L-dopa and decarboxylase inhibitor or reserpine. Quinolinic acid alone decreased the levels of dopamine and noradrenaline, as well as those of c-AMP, and increased those of adrenaline. Treatment with L-dopa/decarboxylase inhibitor reversed the suppressing effect of quinolinic acid on dopamine, but not on noradrenaline. Reserpine alone depleted the contents of dopamine, noradrenaline and adrenaline. It could be concluded from the effects of quinolinic acid and reserpine given together that quinolinic acid suppresses the depletion of amines induced by reserpine. It has been demonstrated that quinolinic acid leads to injuries of nerve-cell bodies in pars compacta of the substantia nigra and in the striatum. Quinolinic acid is a natural metabolite of tryptophan, normally occurring in the liver, kidney and brain (Wolfensberger et al. 1983; Moroni et al. 1984). This compound exhibits convulsant and neuron excitant properties (Stone et al. 1987). It induces a selective pattern of neuronal degeneration both at the site of intracerebral injection (Schwarcz et al. 1983; Stone et al. 1987) and after general (intracardiac) administration (Beskid and Markiewicz 1988). The ability of quinolinic acid to produce neurotoxicity was greater in the striatum than in other parts of the brain. This prompted us to study catecholamine and c-AMP levels in rat brain tissue following quinolinic acid and L-dopa administration, as well as the influence of reserpine on quinolinic acid action.
Animals↗
Quinolinic acid as calcium channel modulator in isolated rat heart preparations.
The effect of quinolinic acid perfusion on isolated rat hearts according to the procedure of Langendorff was studied. In the experiments when the final concentration range of quinolinic acid decreased from 10(-1) to 10(-7) mol/l through intermediate concentrations, a negative inotropic response with the enhancement of the coronary flow was stated. When an isolated heart preparation was perfused with 4 x 10(-3) and 4 x 10(-4) mol/l of a quinolinic acid, a biphasic response of the contractility was visible. In the experiments initial increase and then decrease in the contractility were demonstrated. Therefore, these effects of quinolinic acid were similar to those of the well-known action of the classical calcium channel modulators and may remain the basis of quinolinic acid neuro-excitotoxing activity after intracerebral and general treatment.
Animals↗
The relationship between plasma and brain quinolinic acid levels and the severity of hepatic encephalopathy in animal models of fulminant hepatic failure.
Quinolinic acid is an excitatory, neurotoxic tryptophan metabolite proposed to play a role in the pathogenesis of hepatic encephalopathy. This involvement was investigated in rat and rabbit models of fulminant hepatic failure at different stages of hepatic encephalopathy. Although plasma and brain tryptophan levels were significantly increased in all stages of hepatic encephalopathy, quinolinic acid levels increased three-to sevenfold only in the plasma, CSF, and brain regions of animals in stage IV hepatic encephalopathy. Plasma-CSF and plasma-brain quinolinic acid levels in rats and rabbits with fulminant hepatic failure were strongly correlated, with CSF and brain concentrations approximately 10% those of plasma levels. Moreover, there was no significant regional difference in brain quinolinic acid concentrations in either model. Extrahepatic indoleamine-2,3-dioxygenase activity was not altered in rats in stage IV hepatic encephalopathy, but hepatic L-tryptophan-2,3-dioxygenase activity was increased. These results suggest that quinolinic acid synthesized in the liver enters the plasma and then accumulates in the CNS after crossing a permeabilized blood-brain barrier in the end stages of liver failure. Furthermore, the observation of low brain concentrations of quinolinic acid only in stage IV encephalopathy suggests that the contribution of quinolinic acid to the pathogenesis of hepatic encephalopathy in these animal models is minor.
Animals↗
No changes in central quinolinic acid levels in Alzheimer's disease.
Levels of the endogenous excitotoxin quinolinic acid were measured in brain and lumbar spinal fluid from Alzheimer patients and age-matched controls. Values in post mortem brain tissue, unlike those in spinal fluid, showed considerable variability among subjects. In the control group, frontal cortex and caudate nucleus had higher concentrations of quinolinic acid compared to other regions studied. No significant differences were found between Alzheimer brains and controls in any of the regions analyzed. Studies in lumbar spinal fluid showed no gradient for quinolinic acid along the neuraxis, a trend for increasing levels with normal aging, and no difference between Alzheimer patients and age-matched control subjects. The lack of increased central quinolinic acid levels in Alzheimer's disease does not necessarily negate the possibility of excitotoxins contributing to cell death in this disorder.
Aged↗
Kynurenic acid protects against the neurochemical and behavioral effects of unilateral quinolinic acid injections into the nucleus basalis of rats.
It has recently been demonstrated that kynurenic acid (KYN), an endogenous tryptophan metabolite, provides almost complete protection against the neurotoxic and mnemonic effects of another tryptophan metabolite quinolinic acid (QUIN) on the cell bodies of the nucleus basalis magnocellularis (nbm). The present study further investigated whether unilateral coinjections of KYN and QUIN into the rat nbm antagonized the effects of QUIN alone. Food-deprived rats were pretrained on an eight-arm radial maze, with four arms baited, until choice accuracy stabilized to greater than or equal to 87% correct. Postoperatively, rats were tested on the radial maze for 32 consecutive days. Feeding behavior and locomotor activity were also measured to determine if nonassociative factors accounted for any observed behavioral deficits. QUIN lesions resulted in significantly more working and reference memory errors compared with sham-operated and coinjected animals, which did not differ significantly from each other. There were no reliable group differences in amount of food eaten or locomotor activity. The QUIN group had a reliable decrease in cortical choline acetyltransferase, with no significant changes for the sham and coinjected groups. Results confirm that KYN antagonizes the neurotoxic and mnemonic effects of QUIN alone and suggest that the memory deficits induced by nbm lesions cannot be solely attributed to changes in feeding or locomotor activity.
Animals↗
Quinolinic acid inhibits DOI-induced head shakes in mice.
Quinolinic acid, a metabolite of tryptophan in the kynurenine pathway, inhibited the 5-HT(2A/2C) direct agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino propane hydrochloride (DOI) induced head shakes in mice in a dose-dependent manner. This effect was observed 10 min after intracerebroventricular (i.c.v.) administration of 0.0625-1 microg/mouse. 3-Hydroxyanthranilic acid, which is the immediate stable precursor of quinolinic acid in the kynurenine pathway, showed a similar effect 60-120 min after subcutaneous (s.c.) administration, without showing any effect 10 min after i.c.v. administration or 20-40 min after s.c. administration. These observations suggest that quinolinic acid can alter central effects mediated via 5-HT2A receptors.
3-Hydroxyanthranilic Acid↗
Delayed increases in regional brain quinolinic acid follow transient ischemia in the gerbil.
Excessive activity or release of excitatory amino acids has been implicated in the neuronal injury that follows transient cerebral ischemia. To investigate the metabolism of the endogenous excitotoxin, quinolinic acid, and its potential for mediating cell loss following ischemia, the concentrations of quinolinic acid, L-tryptophan, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid were quantified in gerbil brain regions at different times after 5 or 15 min of ischemia induced by bilateral carotid artery occlusion. Significant elevation of brain tryptophan levels, accompanied by increased 5-hydroxyindoleacetic acid concentrations, occurred during the first several hours of recirculation, but regional brain quinolinic acid concentrations were found either to decrease or remain unchanged during the first 24 h after the ischemic insult. However, significant increases in quinolinic acid concentrations occurred in striatum and hippocampus at 2 days of recirculation after 5 min of ischemia. After a further 4 and 7 days, strikingly large increases in quinolinic acid concentrations were observed in all regions examined, with the highest levels observed in the hippocampus and striatum, regions that also show the most severe ischemic injury. These delayed increases in brain quinolinic acid concentrations are suggested to reflect the presence of activated macrophages, reactive astrocytes, and/or microglia in vulnerable regions during and subsequent to ischemic injury. While the results do not support a role for increased quinolinic acid concentrations in early excitotoxic neuronal damage, the role of the delayed increases in brain quinolinic acid in the progression of postischemic injury and its relevance to postischemic brain function remain to be established.
3,4-Dihydroxyphenylacetic Acid↗
HPLC analysis of quinolinic acid, a NAD biosynthesis intermediate, after fluorescence derivatization in an aqueous matrix.
Quinolinic acid (2,3-pyridine dicarboxylic acid), a biological intermediate in nicotinamide adenine dinucleotide (NAD) biosynthesis in microbes and mammals and a brain excitotoxin, is not fluorescent nor electrochemically active and its detection sensitivity by UV absorption is comparatively low. Quinolinic acid was successfully derivatized in water-based samples by monodansylcadaverine, a fluorescence tag, and analysed by high-performance liquid chromatography (HPLC). No extraction procedure was needed and quinolinic acid was activated by water-soluble carbodiimide and derivatized under mild conditions. As little as 3 pmol (500 pg) of quinolinic acid in 5 microliter of artificial cerebrospinal fluid sample volume could be derivatized and detected at a signal to noise ratio of 3:1. Thus, detection on a mass basis by HPLC after fluorescence derivatization is about 300 times as sensitive as direct determination of quinolinic acid by UV absorbance (500 pg vs 150 ng). A variety of activators, fluorescent tags and reaction solvents and conditions were tested but found to be less effective.
Cadaverine↗
The effect of quinolinic acid administered during pregnancy on the hippocampal formation of rat's offspring (ultrastructural investigation).
The pyramidal cells of CA1 hippocampal area of rat's offspring was ultrastructurally examined after quinolinic acid administration to mothers during the gestational period, in order to mimic the congenital metabolic disturbances resulting from an endogenous excess of quinolinic acid within foetal tissues. Hence, quinolinic acid was administered to mothers intraperitoneally in a dose of 60 mmol, once daily, throughout the entire gestation period. Brain specimens were taken on Day 5 after birth, from experimental and control animals. The only observed change within the pyramidal cells was swelling of both neuronal somata and dendrites, as well as a distinct swelling of astroglia cytoplasm and processes. Besides this, toxic effects, like edema signs, were observed. Neurons of the hippocampal formation were found to be particularly susceptible to quinolinic acid toxicity. The highly vulnerable neurons were located within the CA1-area. The neuronal vulnerability correlates remarkably well with those responding to the excitatory effects of quinolinic acid in electrophysiological experiments (Perkins and Stone 1983 a,b). This region was shown to be rich in NMDA receptors (Cotman et al. 1987; Greenamyre et al. 1984). The susceptibility of neuronal cell bodies of the hippocampal formation of an adult mammalian to the quinolinic acid toxicity, has been investigated with great interest (Schwarcz et al. 1984; Taraszewska et al. 1991; Kida and Matyja 1990; Speciale et al. 1987). Yet there is little information on the course of the foetal development. Hence, in our experiments, quinolinic acid was administered to the mother throughout the gestation period in order to mimic the congenital metabolic disturbances resulting from an excess of quinolinic acid within foetal tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Cerebrospinal fluid levels of quinolinic acid in Huntington's disease and schizophrenia.
The concentration of the endogenous excitotoxin quinolinic acid was determined in the cerebrospinal fluid of drug-free patients suffering from Huntington's disease or schizophrenia (control group). In both diseases, quinolinic acid concentrations were highly variable (less than 4-48 nM) but the mean levels for each disease group were not significantly different from each other or from the quinolinic acid concentration of normal cerebrospinal fluid. Analysis of steady-state cerebrospinal fluid quinolinic acid concentration is unlikely to be of value as a diagnostic tool in Huntington's disease.
Adolescent↗