High levels of quinolinic acid in brain of epilepsy-prone E1 mice

Nakano, Kiwao; Takahashi, Shirō; Mizobuchi, Minoru; Kuroda, Tomoko; Masuda, Katsukichi; Kitoh, Junzoh

doi:10.1016/0006-8993(93)91612-v

Cited by 29 publications

(14 citation statements)

References 9 publications

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“…Although the endogenous QUIN levels, as well as of the enzymes involved in its synthesis, have been found increased in brain of epileptic mouse strains such as E1, DBA/2 and EL (7,27), its role in the pathophysiology of epilepsy remains uncertain. Less questionable, however, is the validity of the QUINinduced seizure model as a pharmacological strategy to evaluate glutamatergic excitotoxicity in vivo, as evidenced by the protection of the classical noncompetitive NMDA antagonist MK-801 against QUINinduced seizures (45,46).…”

Section: Discussionmentioning

confidence: 99%

“…Our group has demonstrated that QUIN, besides its well demonstrated effect as a N-methyl-Daspartate (NMDA) agonist (1), enhances glutamate release from synaptosomal preparations (2) inhibits astrocytic glutamate uptake (2), and decreases the glutamate uptake by synaptic vesicles (3). In physiological conditions, quinolinic acid is found at very low concentrations in the human brain (4,5); it has been, however, involved in the etiology of epilepsy (6)(7)(8). Moreover, in animal experimental models, quinolinic acid induces seizures and death in a dosedependent manner (9).…”

Section: Introductionmentioning

confidence: 99%

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Increase of Adenine Nucleotide Hydrolysis in Rat Hippocampal Slices after Seizures Induced by Quinolinic Acid

et al. 2005

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increase of Adenine Nucleotide Hydrolysis in Rat Hippocampal Slices after Seizures Induced by Quinolinic Acid

et al. 2005

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“…However, overstimulation of the glutamatergic system is involved in many acute and chronic brain diseases such as epilepsy (1)(2)(3). Quinolinic acid (QA), an over stimulator of the glutamatergic system, seems to be involved in the etiology of epilepsy (4,5) and has been proposed to be a useful seizure model in rodents (6,7).…”

Section: Introductionmentioning

confidence: 99%

Intracerebroventricular Guanine-Based Purines Protect Against Seizures Induced by Quinolinic Acid in Mice

2005

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Acute and chronic administration of the nucleoside guanosine have been shown to prevent quinolinic acid (QA) and alpha-dendrotoxin-induced seizures, as well as to impair memory and anxiety in rats and mice. In this study, we investigated the effect of i.c.v. administration of guanine-based purines (GTP, GDP, GMP, and guanosine) against seizures induced by the NMDA agonist and glutamate releaser quinolinic acid in mice. We also aimed to study the effects of the poorly hydrolysable analogs of GTP (GppNHp and GTPgammaS) and GDP (GDPbetaS) in this seizure model. QA produced seizures in 100% of mice, an effect partially prevented by guanine-based purines. In contrast to GTP (480 nmol), GDP (320-640 nmol), GMP (320-480 nmol) and guanosine (300-400 nmol), the poorly hydrolysable analogs of GTP and GDP did not affect QA-induced seizures. Thus, the protective effects of guanine nucleotides seem to be due to their conversion to guanosine. Altogether, these findings suggest a potential role of guanine-based purines for treating diseases involving glutamatergic excitotoxicity.

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“…Given these characteristics, QA is one of the substances used in models studying the effects of overstimulation of the glutamatergic system in the brain. QA has also been suggested to be a neurotoxic endogenous substance involved in the etiology of epilepsy (Nakano et al, 1993), as well as in other diseases like Huntington disease (Ramaswamy et al, 2007) and HIVassociated dementia (Guillemin et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Electrophysiological effects of guanosine and MK-801 in a quinolinic acid-induced seizure model

Torres

Filho

Antunes

et al. 2010

Experimental Neurology

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Quinolinic acid (QA) is an N-methyl-D-aspartate receptor agonist that also promotes glutamate release and inhibits glutamate uptake by astrocytes. QA is used in experimental models of seizures studying the effects of overstimulation of the glutamatergic system. The guanine-based purines (GBPs), including the nucleoside guanosine, have been shown to modulate the glutamatergic system when administered extracellularly. GBPs were shown to inhibit the binding of glutamate and analogs, to be neuroprotective under excitotoxic conditions, as well as anticonvulsant against seizures induced by glutamatergic agents, including QA-induced seizure. In this work, we studied the electrophysiological effects of guanosine against QA-induced epileptiform activity in rats at the macroscopic cortical level, as inferred by electroencephalogram (EEG) signals recorded at the epidural surface. We found that QA disrupts a prominent basal theta (4-10 Hz) activity during peri-ictal periods and also promotes a relative increase in gamma (20-50 Hz) oscillations. Guanosine, when successfully preventing seizures, counteracted both these spectral changes. MK-801, an NMDA-antagonist used as positive control, was also able counteract the decrease in theta power; however, we observed an increase in the power of gamma oscillations in rats concurrently treated with MK-801 and QA. Given the distinct spectral signatures, these results suggest that guanosine and MK-801 prevent QAinduced seizures by different network mechanisms.

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High levels of quinolinic acid in brain of epilepsy-prone E1 mice

Cited by 29 publications

References 9 publications

Increase of Adenine Nucleotide Hydrolysis in Rat Hippocampal Slices after Seizures Induced by Quinolinic Acid

Increase of Adenine Nucleotide Hydrolysis in Rat Hippocampal Slices after Seizures Induced by Quinolinic Acid

Intracerebroventricular Guanine-Based Purines Protect Against Seizures Induced by Quinolinic Acid in Mice

Electrophysiological effects of guanosine and MK-801 in a quinolinic acid-induced seizure model

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