Quinolinic Acid-induced Seizures Stimulate Glutamate Uptake into Synaptic Vesicles from Rat Brain: Effects Prevented by Guanine-based Purines (original) (raw)
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Guanosine and GMP prevent seizures induced by quinolinic acid in mice
Brain Research, 2000
In the mammalian CNS, glutamate and GABA are the principal neurotransmitters mediating excitatory and inhibitory synaptic events, respectively, and have been implicated in the neurobiology of seizures. Guanine-based purines, including the nucleoside guanosine and the nucleotide GMP, have been shown to antagonize glutamatergic activity at the receptor level and the other purine nucleoside adenosine is a well-known modulator of seizure threshold. In the present study we investigated the anticonvulsant effect of i.p. guanosine and GMP against seizures induced by the glutamate agonist quinolinic acid (QA) or the GABA antagonist picrotoxin in mice. Animals were A pretreated with an i.p. injection of saline, guanosine or GMP 30 min before either an i.c.v. injection of 4 ml QA (36.8 nmol) or a subcutaneous injection of picrotoxin (3.2 mg / kg). All animals pretreated with vehicle followed by QA or picrotoxin presented seizures, which were completely prevented by the NMDA antagonist MK-801 and the GABA agonist phenobarbital, respectively. Guanosine and GMP dose-dependently protected against QA-induced seizures, up to 70 and 80% at 7.5 mg / kg, with ED 52.660.4 and 1.760.6 50 mg / kg, respectively. Conversely, neither guanosine, GMP nor MK-801 affected picrotoxin-induced seizures, indicating some degree of specificity towards the glutamatergic system. This study suggests anticonvulsant properties of i.p. guanosine and GMP, which may be related with antagonism of glutamate receptors.
Electrophysiological effects of guanosine and MK-801 in a quinolinic acid-induced seizure model
Experimental Neurology, 2010
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.
Effect of orally administered guanosine on seizures and death induced by glutamatergic agents
Brain Research, 2001
Intraperitoneal guanosine has been shown to prevent quinolinic acid-induced seizures in mice. In this study, we investigated the effect of orally administered guanosine on seizures induced by the glutamate agonists quinolinic acid and kainate, and the endogenous glutamate releaser a-dendrotoxin. Guanosine (7.5 mg / kg, per os), administered 75 min in advance, prevented 70% of seizures induced by i.c.v. quinolinic acid, being as efficient as the NMDA channel blocker MK-801 administered intraperitoneally. Guanosine was ineffective against kainate-induced seizures, but significantly reversed the potentiation of seizures and death caused by the concomitant injection of MK-801. Guanosine also significantly prevented seizures and death induced by i.c.v. a-dendrotoxin, whereas MK-801 and phenobarbital only prevented death. Altogether, our findings underscore the therapeutic potential of oral administration of guanosine for treating diseases involving glutamatergic excitotoxicity, including epilepsy.
In vivo Quinolinic Acid Increases Synaptosomal Glutamate Release in Rats: Reversal by Guanosine
Neurochemical Research, 2005
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-[ 3 H]glutamate release. In this work, we show that i.c.v. QA administration induced seizures in rats and was able to stimulate synaptosomal L-[ 3 H]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-[ 3 H]glutamate uptake. These data provided new evidence on the role of QA and GBPs on glutamatergic system in rat brain.
European Neuropsychopharmacology, 2008
Guanosine, a purine nucleotide, promotes the reuptake of L-glutamate by astrocytes; astrocytic reuptake of glutamate is a major mechanism of its synaptic inactivation. The current experiments showed that guanosine reduced the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor "open-channel" blocker, to raise the threshold voltage for electrically-precipitated tonic hindlimb extension in unstressed intact mice. This modulatory effect may be due to guanosine's removal of glutamate from the synaptic cleft, resulting in a reduced proportion of NMDA receptor-associated ion channels in the open configuration. The modulatory effect of guanosine on MK-801's ability to disrupt rotorod performance in unstressed mice or antagonize electrically-precipitated seizures in stressed mice was not seen. The inability to demonstrate modulation in the rotorod paradigm may reflect the sensitivity of this measure of motor incoordination to MK-801's disruptive effects. Whereas failure to see this effect in our incremental electroconvulsive shock paradigm in stressed mice may be due to the fact that stress and guanosine act in the same direction to reduce MK-801's antiseizure efficacy. Given the phencyclidine model of schizophrenia and its pharmacological actions as a noncompetitive NMDA receptor "open-channel" blocker and guanosine's antagonistic effect on MK-801's antiseizure efficacy in unstressed mice, the current data support development of guanine-based purines for the treatment of at least some aspects of schizophrenia.
Neurotoxicity Research, 2013
Searching for new therapeutic strategies through modulation of glutamatergic transmission using effective neuroprotective agents is essential. Glutamatergic excitotoxicity is a common factor to neurodegenerative diseases and acute events such as cerebral ischemia, traumatic brain injury, and epilepsy. This study aimed to evaluate behavioral and electroencephalographic (EEG) responses of mice cerebral cortex and hippocampus to subconvulsant and convulsant application of NMDA and quinolinic acid (QA), respectively. Moreover, it aimed to evaluate if EEG responses may be related to the neuroprotective effects of NMDA. Mice were preconditioned with NMDA (75 mg/kg, i.p.) and EEG recordings were performed for 30 min. One day later, QA was injected (36.8 nmol/site) and EEG recordings were performed during 10 min. EEG analysis demonstrated NMDA preconditioning promotes spike-wave discharges (SWDs), but it does not display behavioral manifestation of seizures. Animals that were protected by NMDA preconditioning against QA-induced behavioral seizures, presented higher number of SWD after NMDA administration, in comparison to animals preconditioned with NMDA that did display behavioral seizures after QA infusion. No differences were observed in latency for the first seizure or duration of seizures. EEG recordings after QA infusion demonstrated there were no differences in the number of SWD, latency for the first seizure or duration of seizures in animals pretreated with saline or in animals preconditioned by NMDA that received QA. A negative correlation was identified between the number of NMDAinduced SWD and QA-induced seizures severity. These results suggest a higher activation during NMDA preconditioning diminishes mice probability to display behavioral seizures after QA infusion.
Bulletin of Experimental Biology and Medicine, 1989
The results of recent experimental investigations show that quinolinic acid (QA), one of the strongest neuroactive products of the kynurenin metabolism of tryptophan, has a marked excitatory, convulsant, and neurodegenerative action [11, 14]. This action of QA is similar in many respects with the effects of excitatory amino acids (glutamate, aspartate) and of their exogenous analogs (N-methyl-D-aspartate, ibothenate, quisqualate, cainate, etc.). As it has been shown [4, 12, 14], the QA concentration in various brain structures rises during aging and also in epilepsy, senile dementias, Alzheimer's disease, Huntington's chorea, and hepatic coma, and this may be one of the causes of destruction of neurons. Identification and study of the mechanisms of action of QA antagonists is thus an urgent problem. Soem of the investigations to be described below were conducted on dissociated cultures of cells from various brain structures, by means of which the destructive action of QA and its analogs on living neurons could be studied at the cellular level and the protective effect of putative antagonists of this action revealed [8, 13]. Experiments to study the anticonvulsant action of these compounds in situ by their systemic administration and injection into the cerebral ventricles, preceding injection of cytotoxins, are another traditional and effective method of identifying antagonists [1, 6]. The aim of the investigation was to compare the effects of various antagonists on the neurodegenerative action of QA in dissociated cultures of hippocampal cells and on its convulsant action in situ.
Neurochemistry International, 2002
Quinolinic acid (QA) is an endogenous neurotoxin involved in various neurological diseases, whose action seems to be exerted via glutamatergic receptors. However, the exact mechanism responsible for the neurotoxicity of QA is far from being understood. We have previously reported that QA inhibits vesicular glutamate uptake. In this work, investigating the effects of QA on the glutamatergic system from rat brain, we have demonstrated that QA (from 0.1 to 10 mM) had no effect on synaptosomal l-[ 3 H]glutamate uptake. The effect of QA on glutamate release in basal (physiological K + concentration) or depolarized (40 mM KCl) conditions was evaluated. QA did not alter K + -stimulated glutamate release, but 5 and 10 mM QA significantly increased basal glutamate release. The effect of dizolcipine (MK-801), a noncompetitive antagonist of N-methyl-d-aspartate (NMDA) receptor on glutamate release was investigated. MK-801 (5 M) did not alter glutamate release per se, but completely abolished the QA-induced glutamate release. NMDA (50 M) also stimulated glutamate release, without altering QA-induced glutamate release, suggesting that QA effects were exerted via NMDA receptors. QA (5 and 10 mM) decreased glutamate uptake into astrocyte cell cultures. Enhanced synaptosomal glutamate release, associated with inhibition of glutamate uptake into astrocytes induced by QA could contribute to increase extracellular glutamate concentrations which ultimately lead to overstimulation of the glutamatergic system. These data provide additional evidence that neurotoxicity of QA may be also related to disturbances on the glutamatergic transport system, which could result in the neurological manifestations observed when this organic acid accumulates in the brain.
Glutamate uptake shapes low-[Mg2+] induced epileptiform activity in juvenile rat hippocampal slices
Brain Research, 2010
A wide range of data support a role for ambient glutamate (Glu) in epilepsy, although temporal patterns associated with the cellular uptake of Glu have not been addressed in detail. We report on the effects of Glu uptake inhibitors on recurrent seizure-like events (SLEs) evoked by low-[Mg 2+ ] condition in juvenile rat hippocampal slices. Effects were compared for inhibitors such as L-trans-pyrrolidine-2,4-dicarboxylate (tPDC), DL-threo-βbenzyloxyaspartate (DL-TBOA) and dihydrokainic acid (DHK), representing different transporter specificity and transportability profiles. Latency to the first SLE after drug application was shortened by the inhibitors (in % of control: 500 μM tPDC: 54 ± 7, 15 μM DL-TBOA: 74 ± 5, 50 μM DL-TBOA: 70 ± 6, 100 μM DHK: 69 ± 4, 300 μM DHK: 71 ± 7). Further SLEs were frequently aborted by higher inhibitor concentrations applied (500 μM tPDC: 2/6, 50 μM TBOA: 5/5, 100 μM DHK: 6/8, 300 μM DHK: 3/3). Simultaneous field potential and whole-cell voltage recordings showed depolarization-induced inactivation of CA3 pyramidal neurons during inhibitor application. In the presence of inhibitors, the amplitude of forthcoming SLE was also decreased (in % of control: 500 μM tPDC: 66 ± 9, 15 μM DL-TBOA: 88 ± 5, 50 μM DL-TBOA: 59 ± 6, 100 μM DHK: 67 ± 4, 300 μM DHK: 68 ± 1). Dependent on type and concentration of the inhibitor, the duration of the first SLE of drug application either increased (100 μM DHK: 375 ± 90 %; 100 μM tPDC: 137 ± 13 %) or decreased (50 μM TBOA: 62 ± 13 %; 300 μM DHK: 60 ± 15 %) reflecting differences in subtype-specificity or mechanism of action of the inhibitors.