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At least 19 recordsLinked to original sources
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↗
PubMed1999

Indole-3-pyruvic and -propionic acids, kynurenic acid, and related metabolites as luminophores and free-radical scavengers.

Chemiluminescence associated with oxidation by free radicals was investigated in an alkaline, hemin-catalysed hydrogen peroxide system, using the following tryptophan metabolites as radical scavengers: indole-3-pyruvic, indole-3-propionic, kynurenic, xanthurenic and quinaldic acids and 4-hydroxy-quinoline. Light emission from oxidation of the indolic compounds was only partially inhibited by the hydroxyl-radical scavenger DMSO, but strongly suppressed by the superoxide-anion scavenger Tiron, whereas chemi-luminescence generated from kynurenic acid was strongly inhibited by either of these compounds. Light emission from oxidation of kynurenic acid lasts for a surprisingly long period of time: At 0.4 mM and 20 degrees C, luminescence increased for 5 hours and continued at a high rate for more than a day. Comparison of structural analogues indicated that the 4-hydroxyl and carboxyl groups of kynurenic acid are essential for effective light emission, and that an additional 8-hydroxyl residue leading to an intramolecular hydrogen bond diminishes the reaction rate.

Dimethyl Sulfoxide↗
PubMed1990

Increased ratio of quinolinic acid to kynurenic acid in cerebrospinal fluid of D retrovirus-infected rhesus macaques: relationship to clinical and viral status.

Increased concentrations of excitotoxin quinolinic acid in cerebrospinal fluid (CSF) are associated with infection with the human immunodeficiency virus (HIV-1) and have been implicated in the pathogenesis of the acquired immune deficiency syndrome (AIDS) dementia complex. In the present study, inoculation of macaques with D/1/California, an immunosuppressive serotype 1 type D retrovirus, was associated with acute and chronic increases in CSF and serum quinolinic acid concentrations in macaques that had developed SAIDS, a simian disease analogous to AIDS in humans--particularly macaques with demonstrable opportunistic infections. Kynurenic acid, an antagonist of excitatory amino acid receptors as well as the excitotoxic effects of quinolinic acid, was also increased in the CSF of SAIDS macaques, but to a significantly lesser degree than was quinolinic acid (kynurenic acid, 1.8-fold; quinolinic acid, 15.6-fold). CSF quinolinic acid, but not kynurenic acid, was also increased in viremic macaques with SAIDS-related complex (2.4-fold) and asymptomatic virus positive carriers (3.4-fold). Macaques that had recovered from D/1/California infection and were antibody positive and virus negative had normal CSF quinolinic acid and kynurenic acid concentrations. Increased activity of indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway, was indicated in the macaques with SAIDS by reduced serum L-tryptophan and elevated serum L-kynurenine concentrations. Macaques infected with D/1/California may provide a primate model for investigation of the mechanisms involved in increases in CSF quinolinic acid in retrovirus and other infectious diseases, including HIV-1. It remains to be determined whether the increased CSF quinolinic acid concentrations and the increased ratio of quinolinic acid to kynurenic acid have neurological significance or are a useful "marker" of infection.

Animals↗
PubMed2004

Comparative study on the effects of kynurenic acid and glucosamine-kynurenic acid.

Kynurenic acid (KYNA) is the only known endogenous N-methyl-D-aspartate (NMDA) receptor inhibitor and might therefore come into consideration as a therapeutic agent in certain neurobiological disorders. However, its use as a neuroprotective compound is practically excluded because KYNA does not readily cross the blood-brain barrier (BBB). We recently synthetized a new compound, glucosamine-kynurenic acid (KYNA-NH-GLUC), which is presumed to cross the BBB more easily. In this study, the effects of KYNA and KYNA-NH-GLUC on behavior and cortical activity were investigated in adult rats. The results show that (1) on intracerebroventricular application, the behavioral changes induced by KYNA and by KYNA-NH-GLUC are quite similar; (2) on intravenous administration, KYNA (25 mg/kg) has no effect on the somatosensory-evoked cortical potentials, whereas KYNA-NH-GLUC (25 mg/kg) causes transient but appreciable reductions in the amplitudes of the evoked responses within 5 min after application; and (3) the results of in vitro studies demonstrated that both KYNA and KYNA-NH-GLUC reduced the amplitudes of the field excitatory postsynaptic potentials (fEPSPs). These observations suggest that the two compounds have similar effects, but that KYNA-NH-GLUC passes the BBB much more readily than does KYNA. These results imply that the conjugated NH-GLUC is of importance in the passage across the BBB.

Animals↗
PubMed1997

Pretreatment with L-kynurenine, the precursor to the excitatory amino acid antagonist kynurenic acid, suppresses epileptiform activity in combined entorhinal/hippocampal slices.

The kynurenine pathway converts tryptophan into various compounds, including L-kynurenine, which in turn can be converted to the excitatory amino acid receptor antagonist kynurenic acid. The hypothesis that endogenously-produced kynurenic acid could have physiological effects was tested in combined entorhinal/hippocampal slices from adult rats. Specifically, perfusion with L-kynurenine (1 mM) was examined for its ability to suppress epileptiform activity produced by subsequent perfusion with buffer lacking added magnesium (nominal 0 mM magnesium buffer). Importantly, treatment with L-kynurenine did not appear to have depressant effects in itself, but it prevented spontaneous epileptiform activity in all 64 slices subsequently perfused with 0 mM magnesium buffer. In contrast, 45 slices that were not pretreated with L-kynurenine exhibited spontaneous epileptiform activity. These data support the hypothesis that endogenously-produced kynurenic acid can be produced and released in brain slices, where it can suppress excitatory activity in an "anticonvulsant' manner. Therefore, manipulation of the kynurenine pathway might constitute a useful new direction for anticonvulsant drug development.

Animals↗
PubMed2002

Increased phasic activity of dopaminergic neurones in the rat ventral tegmental area following pharmacologically elevated levels of endogenous kynurenic acid.

Kynurenic acid (KYNA) is an antagonist of ionotropic glutamate receptors, preferentially blocking the glycine-site of the N-methyl-D-aspartate (NMDA) receptor. In the present electrophysiological study, the firing pattern of dopamine (DA) neurones of rat ventral tegmental area (VTA) was investigated following pharmacologically elevated endogenous levels of KYNA by means of an inhibitor of kynurenine 3-hydroxylase (PNU 156561A). Pre-treatment with PNU 156561A (40 mg kg-1, i.v., 5-9 h) caused a threefold increase in endogenous KYNA in whole brain levels and also evoked a significant increase in firing rate and bursting activity of VTA DA neurones. Administration of D-cycloserine (2-128 mg kg-1, i.v.), a partial agonist at the glycine-site of the NMDA-receptor, was found to reverse the increase in firing rate and bursting activity as induced by elevated concentrations of KYNA. The electrophysiological effects of elevated KYNA levels were in all essential mimicked by administration of the NMDA-receptor antagonist MK 801 (0.05-1.6 mg kg-1, i.v.). Thus, the effects of elevated endogenous brain KYNA observed in the present study are likely to be carried out by NMDA receptor antagonism. In conclusion, this study shows that an increase in endogenous KYNA levels produces significant actions on the tonic afferent control of the firing pattern of VTA DA neurones. Given the psychotomimetic effects of NMDA-receptor antagonists, e.g. phencyclidine and ketamine, the state of hyperactivity of mesocorticolimbic DA system induced by elevated levels of KYNA may represent a pathophysiological condition analogous to that seen in schizophrenic patients.

Action Potentials↗
PubMed1996

Neuroprotective effect of excitatory amino acid antagonist kynurenic acid in experimental bacterial meningitis.

Sustained high-level exposure to glutamate, an excitatory amino acid neurotransmitter, leads to neuronal death. Kynurenic acid attenuates the toxic effects of glutamate by inhibition of neuronal excitatory amino acid receptors, including the N-methyl-D-aspartate subtype. To evaluate the role of glutamate in causing neuronal injury in a rat model of meningitis due to group B streptococci, animals were treated with kynurenic acid (300 mg/kg subcutaneously once daily) or saline beginning at the time of infection. Histopathologic examination after 24-72 h showed two distinct forms of neuronal injury, areas of neuronal necrosis in the cortex and injury of dentate granule cells in the hippocampus. Animals treated with kynurenic acid showed significantly less neuronal injury (P < .03) in the cortex and the hippocampus than did untreated controls. These results suggest an important contribution of glutamate to neurotoxicity in this animal model of neonatal meningitis.

Animals↗
PubMed1990

Determination of extracellular kynurenic acid in the striatum of unanesthetized rats: effect of aminooxyacetic acid.

Kynurenic acid (KYNA) production from its bioprecursor L-kynurenine (KYN) was assessed in vivo by intrastriatal microdialysis in freely moving rats. In the absence of KYN, the extracellular concentration of KYNA was below the limit of assay sensitivity (i.e. less than 8 pmol/30 microliters). In the presence of KYN (50-2000 microM), KYNA concentration in the dialysate increased continuously to reach steady-state levels after 2h of perfusion. Introduction of the unspecific transaminase inhibitor aminooxyacetic acid (AOAA) through the dialysis probe caused a progressive decrease of extracellular KYNA, which reached dose-dependent minimal levels within 2 h. One mM AOAA caused an almost complete depletion of KYNA in the dialysate. These data demonstrate that extracellular KYNA can be assessed by microdialysis and that AOAA can be used as a tool to examine the neurobiology of KYNA in awake, freely moving animals.

Aminooxyacetic Acid↗
PubMed1984

Kynurenic acid blocks neurotoxicity and seizures induced in rats by the related brain metabolite quinolinic acid.

Kynurenic acid (KYNA) was tested as an antagonist of the neurotoxic and epileptogenic effects of the metabolically related brain constituent quinolinic acid (QUIN). In the rat striatum, KYNA blocked the neurotoxic effects of QUIN in preference to those of other excitotoxins. In the hippocampus, KYNA antagonized both the neurodegeneration and seizures caused by the local application of QUIN. These properties of KYNA raise the possibility of a functional link between KYNA and QUIN in the brain which may be of relevance for an understanding of human neurodegenerative disorders.

Animals↗
PubMed2006

Effects of COX-1 and COX-2 inhibitors on the firing of rat midbrain dopaminergic neurons--possible involvement of endogenous kynurenic acid.

Kynurenic acid (KYNA) is an endogenous glutamate-receptor antagonist with a preferential action at the glycine-site of the NMDA-receptor. In the present in vivo study, the importance of brain KYNA to modulate the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) was analyzed by utilizing the decrease in brain KYNA formation induced by the cyclooxygenase (COX)-2 inhibitor parecoxib. A reduction in brain KYNA concentration (39-44%) by parecoxib (25 mg/kg, i.v., 1 h or, i.p., 3.5 h) was associated with a decreased firing rate and burst firing activity. In concordance, an increase in brain KYNA concentration (150-300%), induced by the COX-1 inhibitor indomethacin (50 mg/kg, i.v., 1 h or, i.p., 3.5 h), produced opposite effects, that is, increased firing rate and burst firing activity. The decrease and increase in neuronal firing of VTA DA neurons by the COX-inhibitors was reversed by L-701,324 (antagonist at the NMDA-glycine site; 0.06-2 mg/kg, i.v.) and by D-cycloserine (partial agonist at the NMDA-glycine site; 2-32 mg/kg, i.v.), respectively. In addition, the parecoxib-induced decrease in firing rate and burst firing activity was effectively blocked by pretreatment with kynurenine (5 mg/kg, i.p., 30 min), the immediate precursor of KYNA. Present results suggest that the action of COX-inhibitors on the firing of VTA DA neurons are linked to their effects on KYNA formation and that endogenous KYNA is tonically modulating the neuronal activity of VTA DA neurons. Such a modulatory action of KYNA should be of importance for the functioning of mesocorticolimbic DA pathway.

Action Potentials↗
PubMed1988

The excitatory amino acid antagonist kynurenic acid administered after hypoxic-ischemia in neonatal rats offers neuroprotection.

The neuroprotective effect of kynurenic acid, an unspecific antagonist of excitatory amino acid receptors, was evaluated in a model of hypoxic-ischemia in neonatal rats. One-week-old rats were subjected to ligation of the left carotid artery and exposure to 7.7% O2/92.3% N2 for 2 h. Kynurenic acid (300 mg/kg) was administered i.p. immediately after the period of hypoxic-ischemia in one group (n = 32) and compared with saline-treated (n = 27). After 2 weeks the rats were sacrificed and the brain damage evaluated by comparing the weight of the lesioned and unlesioned hemispheres. In rats receiving kynurenic acid the reduction in weight of the lesioned hemisphere was 25.4 +/- 3.3% as compared to 37.8 +/- 3.6% in saline-treated controls (P less than 0.001). The results suggest that excitatory amino acids are involved in the development of postischemic damage in the immature brain.

Animals↗
PubMed1991

A comparison of excitotoxic lesions of the basal forebrain by kainate, quinolinate, ibotenate, N-methyl-D-aspartate or quisqualate, and the effects on toxicity of 2-amino-5-phosphonovaleric acid and kynurenic acid in the rat.

1. It has been suggested that an NMDA1 receptor subtype might be activated by N-methyl-D-aspartate (NMDA) and ibotenate and an NMDA2 subtype by NMDA or quinolinate, and that the NMDA2 site might be more susceptible to blockade by kynurenic acid. 2. Experiments were carried out to examine the ability of 2-amino-5-phosphonovaleric acid (AP5) and kynurenic acid to antagonize the neurotoxic properties of kainate, ibotenate, NMDA, quinolinate and quisqualate injected into the rat basal forebrain. 3. Following histological analysis of the injection sites, lesion volume was assessed parametrically. Each of the toxins except quisqualate was found to make lesions of parvocellular neurones within the basal forebrain with a relative order of potency: kainate much greater than quinolinate greater than ibotenate = NMDA. 4. Equimolar doses of AP5 abolished the toxicity produced by quinolinate and NMDA; toxicity to kainate and ibotenate was attenuated to approximately 40% of the toxin-alone condition. 5. The antagonistic properties of kynurenate were dose-dependent: equimolar kynurenate had no effect on quinolinate but attenuated the actions of ibotenate, kainate and NMDA; 2 x equimolar kynurenate had no effect on quinolinate or ibotenate but attenuated the toxicity of kainate and NMDA; and 3 x equimolar kynurenate had no effect on the toxicity of kainate or ibotenate, attenuated the actions of NMDA and abolished the toxic action of quinolinate. 6. The results are discussed in terms of the actions of the various toxins at different receptors, differentially sensitive to AP5 and kynurenate.

2-Amino-5-phosphonovalerate↗
PubMed1984

Actions of excitatory amino acids and kynurenic acid in the primate hippocampus: a preliminary study.

Orthodromic evoked potentials of CA1 pyramidal cells were studied in superfused slices of marmoset hippocampus. N-methylaspartate, quinolinic acid and quisqualic acid depressed the responses, but only the former two compounds appeared to be antagonized by 2-amino-5-phosphonovalerate. Kynurenic acid also reduced the orthodromic evoked responses but had no effect on antidromic potentials, the blocking action therefore probably resulting from an interference with synaptic transmission. The study reveals receptors for N-methylaspartate, quisqualate, quinolinate and kynurenic acid in the primate hippocampus broadly comparable with those previously studied in non-primate vertebrates.

Amino Acids↗
PubMed1988

The effects of the excitatory amino acid antagonist kynurenic acid on synaptic transmission to supraoptic neuroendocrine cells.

The magnocellular neuroendocrine system of the mammalian hypothalamus regulates numerous physiological functions by releasing the peptide hormones oxytocin and vasopressin from the neurohypophysis. Although several substances are known to promote hormone release, relatively little research has been aimed at testing the hypothesis that excitatory amino acids (EAAs) mediate synaptic transmission in this neuroendocrine system. In the present experiments, intracellular recordings in slices of rat hypothalamus revealed that kynurenic acid, a specific antagonist of EAA receptors, strongly and reversibly blocked excitatory postsynaptic potentials (EPSPs) in supraoptic neurons. The profound antagonism of EPSPs by kynurenic acid strongly suggests that EAAs may be an important class of fast excitatory neurotransmitter within this central regulatory nucleus.

Action Potentials↗
PubMed2005

Systemically administered glucosamine-kynurenic acid, but not pure kynurenic acid, is effective in decreasing the evoked activity in area CA1 of the rat hippocampus.

The metabolism of tryptophan along the kynurenine pathway yields several neuroactive intermediates, including kynurenic acid, which is one of the few known endogenous N-methyl-d-aspartate receptor inhibitors; in parallel with this, it is an alpha7 nicotinic acetylcholinergic receptor antagonist. On the basis of these properties, kynurenic acid might therefore come into consideration as a therapeutic agent in certain neurobiological disorders. However, the use of kynurenic acid as a neuroprotective agent is practically excluded because kynurenic acid hardly crosses the blood-brain barrier. We recently synthetized a new compound, glucosamine-kynurenic acid, which is presumed to cross the blood-brain barrier more easily. In this study, the effects of systemically administered kynurenic acid and glucosamine-kynurenic acid on CA3 stimulation-evoked population spike activity in region CA1 of the rat hippocampus were compared. The effect of kynurenic acid or glucosamine-kynurenic acid was augmented by probenecid (200 mg/kg), which inhibits kynurenic acid excretion from the cerebrospinal fluid. The results showed that, while kynurenic acid administered i.p. or i.v. in doses of 17, 34, 68 or 136 micromol/kg did not cause any observable change in the animals, 136 micromol/kg glucosamine-kynurenic acid (either i.p. or i.v.) resulted in the sudden death of all the animals. The dose of 68 micromol/kg i.v., but not i.p., resulted in a sudden stoppage of breath, but the animals could be reanimated. As small a dose of glucosamine-kynurenic acid as 17 micromol/kg i.p. resulted in a reduction in population spike amplitudes; this effect was further augmented by probenecid, whereas neither 17 micromol/kg nor higher doses of pure kynurenic acid had a similar effect. The results presented here suggest that glucosamine-kynurenic acid passes the blood-brain barrier much more readily than does kynurenic acid.

Action Potentials↗