Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurological dysfunction, seizures and brain atrophy occur in a broad spectrum of acute and chronic neurological diseases. In certain instances, over-stimulation of N-methyl-D-aspartate receptors has been implicated. Quinolinic acid (QUIN) is an endogenous N-methyl-D-aspartate receptor agonist synthesized from L-tryptophan via the kynurenine pathway and thereby has the potential of mediating N-methyl-D-aspartate neuronal damage and dysfunction. Conversely, the related metabolite, kynurenic acid, is an antagonist of N-methyl-D-aspartate receptors and could modulate the neurotoxic effects of QUIN as well as disrupt excitatory amino acid neurotransmission. In the present study, markedly increased concentrations of QUIN were found in both lumbar cerebrospinal fluid (CSF) and post-mortem brain tissue of patients with inflammatory diseases (bacterial, viral, fungal and parasitic infections, meningitis, autoimmune diseases and septicaemia) independent of breakdown of the blood-brain barrier. The concentrations of kynurenic acid were also increased, but generally to a lesser degree than the increases in QUIN. In contrast, no increases in CSF QUIN were found in chronic neurodegenerative disorders, depression or myoclonic seizure disorders, while CSF kynurenic acid concentrations were significantly lower in Huntington's disease and Alzheimer's disease. In inflammatory disease patients, proportional increases in CSF L-kynurenine and reduced L-tryptophan accompanied the increases in CSF QUIN and kynurenic acid. These responses are consistent with induction of indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway which converts L-tryptophan to kynurenic acid and QUIN. Indeed, increases in both indoleamine-2,3-dioxygenase activity and QUIN concentrations were observed in the cerebral cortex of macaques infected with retrovirus, particularly those with local inflammatory lesions. Correlations between CSF QUIN, kynurenic acid and L-kynurenine with markers of immune stimulation (neopterin, white blood cell counts and IgG levels) indicate a relationship between accelerated kynurenine pathway metabolism and the degree of intracerebral immune stimulation. We conclude that inflammatory diseases are associated with accumulation of QUIN, kynurenic acid and L-kynurenine within the central nervous system, but that the available data do not support a role for QUIN in the aetiology of Huntington's disease or Alzheimer's disease. In conjunction with our previous reports that CSF QUIN concentrations are correlated to objective measures of neuropsychological deficits in HIV-1-infected patients, we hypothesize that QUIN and kynurenic acid are mediators of neuronal dysfunction and nerve cell death in inflammatory diseases. Therefore, strategies to attenuate the neurological effects of kynurenine pathway metabolites or attenuate the rate of their synthesis offer new approaches to therapy.
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PMID:Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. 142 88

Quinolinic acid (QUI), a structural analogue of neurotransmitters such as L-glutamate and L-aspartate, may act as an 'excitotoxin' when it is abundant in the brain. The compound has been causally related to various neurodegenerative disorders, including epilepsy. We tested the capacity of the brains of epilepsy-prone El mice to synthesize QUI. The activity of 3-hydroxyanthranilate 3,4-dioxygenase in the cerebral cortex of El mice was about 17 times that of ddY mice, the parent strain of El mice. The activity of this enzyme was undetectable in brains of BALB/cA mice and C3H/HeN mice. In El mice the sexes had comparable enzyme activity. The enzyme activity increased gradually as the animals aged. An injection of endotoxin caused a further increase in the enzyme activity. The enzyme activity in the spleen of El mice did not differ from that of ddY mice, and endotoxin did not affect the enzyme activity in the spleen. No strain-difference was observed in the activity of quinolinate phosphoribosyltransferase, a QUI-degrading enzyme, in the cerebral cortex. These results suggest that an increase in the synthesis of QUI in the brain is involved in the pathogenesis of epileptic seizures in El mice.
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PMID:Abnormally high activity of 3-hydroxyanthranilate 3,4-dioxygenase in brain of epilepsy-prone El mice. 161 5

Quinolinic acid (QUIN) is a neurotoxin and convulsant when injected directly into the brains of experimental animals and as such has been implicated in the etiology of human seizure disorders. In the present study, we quantified QUIN in cerebrospinal fluid (CSF) and in spiking (focus) and nonspiking (nonfocus) regions of surgically resected human temporal neocortex. L-tryptophan (L-TRP), the putative precursor of QUIN, was also measured in brain, along with CSF concentrations of L-TRP, 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA). In brain tissue, no differences were found in the concentrations of QUIN and L-TRP between focus and nonfocus regions in 15 pairs of samples. No differences were found in CSF, L-TRP, 5-HIAA, or HVA concentrations between 11 neurologically normal controls and 15 interictal (no seizures for greater than 24 h) and 20 postictal (within 50 min of seizure) samples from epileptic patients. However, CSF QUIN concentrations were significantly lower (32%) in the epileptic patients as compared with controls, which may indicate a generalized disturbance in brain QUIN metabolism or perhaps a response to antiepileptic drugs.
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PMID:Quinolinic acid concentrations in brain and cerebrospinal fluid of patients with intractable complex partial seizures. 169 Jun 39

Administration of reserpine, trifluperidol, chlorpromazine, haloperidol, spiroperidol, and thioproperazine to adult mice shortened the latency and increased the number of animals with clonic seizures induced by 1-kynurenine sulfate or its metabolite quinolinic acid. Haloperidol dose-dependently intensified kynurenine-induced seizures and did not alter pentylenetetrazole seizures. Dopamine abolished the effect of haloperidol while serotonin was ineffective. Pretreatment with 6-hydroxydopamine potentiated kynurenine-induced seizures, but not quinolinic acid-induced seizures. The seizure thresholds of kynurenine and quinolinic acid were not affected by pretreatments with yohimbine, clonidine, piperoxan, phentolamine and tricyclic antidepressants. Apomorphine and amphetamine (i.p.), noradrenaline and adrenaline (i.c.v.) possess anticonvulsant action against kynurenine and not against quinolinic acid. The data obtained suggest a similarity of kynurenine and known convulsants in the involvement of the catecholaminergic processes in their convulsant action. Quinolinic acid markedly differs from kynurenine in its mechanism of action as indicated by their interactions with numerous endogenous substances.
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PMID:Effect of catecholaminergic drugs on quinolinate- and kynurenine-induced seizures in mice. 214 73

Quinolinic acid (QUIN), an endogenous neuroactive metabolite of tryptophan, administered i.c.v. in doses of 45, 90, 180, and 270 nmol in rabbits, demonstrated an excitatory action on the sleep-wake cycle and behaviour. Doses of 90 and 180 nmol completely abolished the paradoxical sleep phase and induced a 5-fold decrease in the duration of deep slow wave sleep (dSWS) in the first hour of the experiment. Light slow wave sleep (1SWS) duration was not altered. Sniffing behaviour was markedly activated by 180 nmol of QUIN. A dose of 270 nmol completely blocked sleep, diminished the restoration of sleep, induced panic behaviour and, in some animals, induced generalized tonic seizures. Data suggest an excitatory action of QUIN on NMDA receptors involved in the regulation of the sleep-wake cycle in the rabbit.
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PMID:Effect of quinolinic acid on wakefulness and sleep in the rabbit. 214 74

Quinolinic acid (QUIN) is an endogenous, excitotoxic amino acid which is currently under investigation as a possible etiological factor in human neurodegenerative disorders such as Huntington's disease and epilepsy. We explored certain aspects of this hypothesis, using the adult rat as an experimental animal. After intrastriatal infusions of [3H]QUIN, radioactivity was cleared from the injected region with an apparent half-life of 22 min. To 2 h after injection, all radioactivity recovered from the striatum corresponded to unmetabolized QUIN. Consistent with these data was the lack of significant uptake of [3H]QUIN by slices or crude synaptosomes prepared from rat hippocampus or striatum. When applied intravenously, a high dose of QUIN (450 mg/kg) caused relatively minor seizure-related EEG changes and no signs of neuronal degeneration. Direct measurements indicated negligible penetration of the blood-brain barrier by QUIN. The lack of an effective inactivation mechanism for extracellular QUIN in the brain negates QUIN's proposed role as a classical neurotransmitter substance, but may be of significance for the postulated effects of this compound in neurodegenerative diseases. An important role of blood-borne QUIN or QUIN precursors in human disorders cannot be ruled out at present; although the brain appears to be well protected by the blood-brain barrier from an acute elevation of blood QUIN, a possible breakdown of the barrier under pathologic conditions and the effects of chronic elevations of blood QUIN remain to be examined.
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PMID:Studies on the disposition of quinolinic acid after intracerebral or systemic administration in the rat. 623 46

Quinolinic acid appeared to be the only kynurenine metabolite among tested (L- and DL-kynurenine sulfate, kynurenic and nicotinic acids, nicotinamide) which induced locomotor excitation and clonic seizures in rats whereas all of them exerted convulsant action in mice. Excitatory 1-glutamic and 1-aspartic amino acids and inhibitory amino acids GABA, 1-glycine and taurine did not induce either excitation of seizures in rats but did so in mice. Moreover, GABA, 1-glycine and taurine induced obvious sedation, side position and discoordination in rats. Convulsants strychnine sulfate and pentylenetetrazol induced seizures both in rats and in mice. The differences between mice and rats seem to be due to better availability of hippocampus for the intraventricularly administered drugs in mice. Mice seem to be preferable for studies with intraventricularly administered excitatory amino acids including kynurenines, whereas rats are preferable for inhibitory amino acids.
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PMID:[Stimulatory effects of intraventricular administration of kynurenines, amino acids, and convulsants: differences between rats and mice]. 715 52

Quinolinic acid (QA) has been used as a model for experimental overstimulation of the glutamatergic system. Glutamate uptake is the main mechanism involved in the maintenance of extracellular glutamate below toxic levels. Guanosine systemically administered prevents quinolinic acid-induced seizures in adult mice and increases basal glutamate uptake by cortical astrocyte culture and slices from young rats. The immature brain differs from the adult brain in its susceptibility to seizures, seizure characteristics, and responses to antiepileptic drugs (AED). Here we investigated the effect of guanosine p.o. on QA-induced seizures in young rats (P12-14) and upon ex vivo glutamate uptake by cortical slices from these animals. I.c.v. infusion of 250 nmol QA induced seizures in all animals and decreased glutamate uptake. I.p. injection of MK-801 and phenobarbital 30 min before QA administration prevented seizures in all animals. Guanosine (7.5 mg/kg) 75 min before QA prevented seizures in 50% of animals as well as prevented the decrease of glutamate uptake in the protected animals. To investigate if the anticonvulsive effect of guanosine was specific for QA-induced seizures, the picrotoxin-induced seizures model was also performed. Pretreatment with phenobarbital i.p. (60 mg/kg-30 min) prevented picrotoxin-induced seizures in all animals, whereas guanosine p.o. (7.5 mg/kg-75 min) and MK-801 i.p. (0.5 mg/kg-30 min) had no effect. Thus, guanosine protection on the QA-induced seizures in young rats and on the decrease of glutamate uptake showed some specificity degree towards the QA-induced toxicity. This points that guanosine could be considered for treatments of epilepsy, and possibly other neurological disorders in children.
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PMID:Quinolinic acid promotes seizures and decreases glutamate uptake in young rats: reversal by orally administered guanosine. 1526 4

Quinolinic acid (QUIN), an endogenous convulsant compound, overstimulates the glutamatergic system stimulating N-methyl-D-aspartate receptors, enhancing glutamate release and inhibiting glutamate uptake. Glutamate releases the neuroprotector adenosine, which in turn reduces glutamate release and depresses the neuronal activity. Additionally, adenine nucleotides are an important source of adenosine, by action of ecto-nucleotidases. Here we evaluated the adenine nucleotide hydrolysis in hippocampal slices of adult rats in different times after seizures induced by QUIN. After 45 min, there was an increase of ATP and ADP hydrolysis. After 5 h, there was an increase of ATP, ADP and AMP hydrolysis. After 12 h, there was an increase only of ATP hydrolysis. After 24 h, all hydrolysis returned to control levels. As slice preparations maintain tissue integrity, this study indicates, more than previously observed with synaptosomal preparations, that the extracellular production of the neuroprotector adenosine may be involved in brain responses to seizures.
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PMID:Increase of adenine nucleotide hydrolysis in rat hippocampal slices after seizures induced by quinolinic acid. 1601 83

Glutamate, the main excitatory neurotransmitter in the mammalian central nervous system (CNS), plays important role in brain physiological and pathological events. Quinolinic acid (QA) is a glutamatergic agent that induces seizures and is involved in the etiology of epilepsy. Guanine-based purines (GBPs) (guanosine and GMP) have been shown to exert neuroprotective effects against glutamatergic excitotoxic events. In this study, the influence of QA and GBPs on synaptosomal glutamate release and uptake in rats was investigated. We had previously demonstrated that QA "in vitro" stimulates synaptosomal L-[3H]glutamate release. In this work, we show that i.c.v. QA administration induced seizures in rats and was able to stimulate synaptosomal L-[3H]glutamate release. This in vivo neurochemical effect was prevented by i.p. guanosine only when this nucleoside prevented QA-induced seizures. I.c.v. QA did not affect synaptosomal L-[3H]glutamate uptake. These data provided new evidence on the role of QA and GBPs on glutamatergic system in rat brain.
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PMID:In vivo quinolinic acid increases synaptosomal glutamate release in rats: reversal by guanosine. 1607 13


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