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)

The editing status of mRNA at the Q/R site of the glutamate receptor subtypes -A, -B, -5 and -6 modulates channel conductivity and ion selectivity of glutamate operated ion channels [4,15,26,30]. In order to investigate whether a modification of this editing process may be involved in kindling epileptogenesis, the percentage of edited variant was determined in the hippocampus of kindled rats and compared to the percentage in control animals. In the latter, GluR-A mRNA was detected only in the unedited form (with detection threshold for edited form < 0.7%), whereas GluR-B was completely edited (> 99%). For percentages were not significantly changed in Schaffer collateral/commissural pathway kindled animals that were sacrificed 24 h after the last generalized seizure. It is concluded that the increased sensitivity for the induction of seizures characteristic for Schaffer collateral kindled animals is not related to a less selective or less efficient mRNA editing process of the different glutamate receptor subunits in the hippocampus.
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PMID:Editing status at the Q/R site of glutamate receptor-A, -B, -5 and -6 subunit mRNA in the hippocampal kindling model of epilepsy. 776 99

As seizure propagation within limbic structures is mediated in part by a small area of deep prepiriform cortex (area tempestas), we investigated the role of area tempestas in modulating hippocampal injury induced by systemic kainate administration. Injury was quantitated by counting the numbers of neurons that stained for the 72,000 mol. wt heat shock protein and with acid-fuchsin dye. Status epilepticus induced these markers of neuronal injury in the CA1 and CA3a regions of the hippocampus, thalamus, piriform cortex and the amygdaloid complex. Microinjection of 2-amino-7-phosphonoheptanoic acid, a competitive antagonist of the N-methyl-D-aspartate subclass of the glutamate receptor, into area tempestas prior to systemic administration of kainate attenuated both heat shock protein induction and acid-fuchsin labeling in CA1 and CA3a pyramidal neurons without reducing the duration of electrographic seizures. Injections of bicuculline, a GABA antagonist, into area tempestas produced hippocampal damage when given with subcytotoxic doses of intravenous kainate. Thus, area tempestas may be a uniquely sensitive anatomical structure involved not just in seizure propagation but also in modulating the extent and pattern of damage induced in hippocampal neurons as a result of prolonged, systemically induced seizures. These effects are due in part to excitatory and inhibitory projections to neurons in area tempestas.
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PMID:Deep prepiriform cortex modulates kainate-induced hippocampal injury. 783 80

We tested the hypothesis that glutamate receptor antagonists increase the dose of lidocaine required to induce seizure activity. Sprague-Dawley rats were anesthetized with halothane in 40% O2/balance N2 and mechanically ventilated. After surgical preparation, halothane was discontinued. Normocapnia, normoxia, and normothermia were maintained. The electroencephalogram (EEG) and arterial blood pressure were monitored continuously. Rats were then randomized to one of six groups (control, one of three intravenous [i.v.] bolus doses of the competitive glutamate N-methyl-D-aspartate [NMDA] receptor antagonist CGS 19755, or one of two i.v. bolus and continuous infusion regimens of the competitive glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA] receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo-(F)quinoxalline [NBQX]). Thirty minutes after onset of CGS 19755 or NBQX administration (end-tidal halothane < 0.2%), rats received a continuous i.v. infusion of 1.5% lidocaine until EEG seizures occurred. The duration of the infusion (min) and total lidocaine dose (mg/kg) administered were recorded. CGS 19755 increased the lidocaine seizure threshold in a log-linear dose-dependent fashion (P < 10(-6)). The largest dose of CGS 19755 (112.5 mg/kg) increased the time to initial EEG seizure activity more than twofold (e.g., control = 12.6 +/- 2.6 min; CGS 19755 = 28.6 +/- 6.9 min). The effect of AMPA receptor antagonism was less obvious because treatment resulted in an EEG morphology dissimilar to that observed in the CGS 19755 or control groups. Our findings indicate that competitive NMDA receptor antagonists (e.g., CGS 19755) increase the dose of lidocaine required for seizures.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glutamatergic antagonism: effects on lidocaine-induced seizures in the rat. 794 78

The expression level of the mRNAs encoding the Flip and Flop versions of the AMPA-selective glutamate receptor subunits A, B, C and D was studied using in situ hybridization in the hippocampus of rats kindled by Schaffer collateral/commissural fibre stimulation. The expression levels of the Flip variant of GluR-A, B and C mRNAs were bilaterally enhanced in the dentate granule neurons of fully kindled animals 24 h after the last seizure. These changes were already observed after the sixth kindling stimulation (preconvulsive-stage), but not after a single afterdischarge. Four weeks after the last seizure, when the animals were still hypersensitive to kindling stimulations, only GluR-A Flip expression was enhanced. These results suggest that kindling epileptogenesis is accompanied by an increased number and enhanced sensitivity of the expressed AMPA type glutamate receptors in the fascia dentata, leading to an enhanced excitatory synaptic transmission which may contribute to the process of kindling epileptogenesis.
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PMID:Rat hippocampal kindling induces changes in the glutamate receptor mRNA expression patterns in dentate granule neurons. 795 92

1. Rats were chemically kindled by systemic administration of pentylenetetrazole (PTZ) every 48 h. An initially subthreshold dose that did not elicit a motor response when first applied caused severe epileptiform seizures when the animal was kindled. Once kindled, animals continued to respond to the initially subthreshold dose with a full-blown seizure for > 2 mo, even when regular administration ceased for > or = 1 mo. 2. In neocortical slices taken from kindled rats, low-intensity electrical stimulation evoked generation of prolonged (hundreds of milliseconds) paroxysmal extracellular field potentials and intracellular depolarizing potentials, indicating synchronized activity of large populations of neurons. This hyperexcitability usually appeared as an all-or-none event of variable latency. In a few cases it increased gradually with increasing stimulus intensity. The intensity of the paroxysmal response was greatly enhanced by application of gamma-aminobutyric acid-A (GABAa) receptor blockers to the bath. 3. Intracellular recordings revealed that PTZ-kindled cells differ from normal cells in their higher input resistance (42.4 + 13.6 vs. 26.4 + 9.2 M omega, mean +/- SE). Spikes generated by kindled cells differed significantly from those in normal cells in that they were of longer duration (1.65 + 0.3 vs. 1.40 + 0.15 ms) and had a slower maximal rate of fall (103 + 29.7 vs. 126 + 20.8 volts/s). 4. Injection of the lidocaine derivative QX-314 to the recorded neurons (100 mM) blocked the fast Na+ spikes. Under these conditions slow spikes, probably Ca2+ mediated, were evoked from the soma in neurons from kindled but not from normal cortex. 5. The role of N-methyl-D-aspartate (NMDA) receptors in generating paroxysmal events was evaluated by application of 20 microM 2-amino-5-phosphonovaleric acid, a specific blocker of this glutamate receptor type. Blockage of NMDA receptors cut short the paroxysmal field potentials but did not prevent their generation. Intracellularly recorded paroxysmal responses were also cut short but not abolished by intracellular hyperpolarization. 6. In slices from kindled animals intracellular responses in neurons of deeper layers differed markedly from those of superficial cells. In deep neurons, responses resembled those generated by neocortical neurons exposed to GABAergic blockers. A low-intensity stimulus to the white matter evoked an excitatory postsynaptic potential (EPSP) followed with variable latency by a paroxysmal depolarizing shift that reversed at suprathreshold membrane potentials and on which superimposed repetitive firing was always evident.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Long-term changes in neocortical activity after chemical kindling with systemic pentylenetetrazole: an in vitro study. 796 34

Glutamate has traditionally been regarded as an excitatory neurotransmitter. Synaptic activation of ionotropic glutamate receptors mediates fast EPSPs in the CNS. Moreover, activation of metabotropic glutamate receptors (mGluRs), which are coupled to second messenger effector systems via GTP-binding proteins (G-proteins), results in the expression of slow EPSPs. We have now examined the response of basolateral amygdala (BLA) neurons to activation of postsynaptic mGluRs. In approximately 78% of BLA neurons examined, activation of postsynaptic mGluRs results in membrane hyperpolarization and an associated decrease in membrane input resistance or a hyperpolarization followed by a depolarization associated with an increase in input resistance. The purpose of this study was to address the mechanisms underlying the membrane hyperpolarization. Here, we report that the ACPD-induced hyperpolarization is insensitive to TTX, is dependent on extracellular K+ concentrations, and has a reversal potential (-84 mV) close to that estimated from the Nernst equation for an increase in a K+ conductance. In addition, the ACPD response is resistant to (1) intracellular chloride loading, (2) the GABAB receptor antagonist CGP55845A, (3) the ACh receptor antagonist atropine, and (4) the ionotropic glutamate receptor antagonists CNQX and APV. These data suggest that the hyperpolarization results from a direct activation of postsynaptic mGluRs on neurons of the BLA. Furthermore, we performed studies that suggest that the hyperpolarization is G-protein mediated and results from activation of a TEA-sensitive, calcium-dependent potassium conductance. The sensitivity of this conductance to thapsigargin further suggests that this response requires the release of calcium from intracellular stores. In summary, these data suggest a role for glutamate as an inhibitory transmitter in the BLA during periods of metabotropic glutamate receptor activation. In nuclei such as the BLA that are exquisitely sensitive to seizure induction, an inhibitory response to glutamate may act to delay the onset of epileptogenesis.
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PMID:Activation of postsynaptic metabotropic glutamate receptors by trans-ACPD hyperpolarizes neurons of the basolateral amygdala. 796 9

Kindling refers to a phenomenon in which repeated application of initially subconvulsive electrical stimulations produces limbic and clonic motor seizures of progressively increasing severity. Once established, the increased excitability is lifelong. Enhanced function of synapses using the NMDA subtype of glutamate receptor could contribute to the expression of the increased excitability. We previously found that CA3 pyramidal cells of hippocampus of kindled animals exhibit a selective and long-lasting (1 month) increased sensitivity to NMDA-evoked depolarization. The goal of this study was to develop a molecular explanation of the enhanced sensitivity to NMDA. We used radioligand binding studies of membranes isolated from microdissected regions of hippocampus including fascia dentata, CA3, and CA1. We also used quantitative in situ hybridization with subtype-specific riboprobes or oligonucleotides to determine whether increased expression of one or more of the genes encoding NMDA receptors was present in hippocampal granule and pyramidal cells of kindled animals. When studied 28 d after the last evoked seizure, we found that kindling induced a 2.8-fold increase in the number of binding sites for the competitive NMDA receptor antagonist 3-[(+/-)-2-(carboxypiperazine-4-yl)][1,2-3H-]propyl-1-phosphonic acid (3H-CPP). This increase was confined to region CA3 within the hippocampus. Similar, though much smaller, changes were detected 24 hr after the last evoked seizure. Surprisingly, no changes in the binding of another competitive NMDA receptor antagonist, cis-4-(phosphonomethyl)-2-3H-piperidinecarboxylate (3H-CGS-19755), were detected at either time point in any hippocampal region. Transcript levels of the NMDA receptor genes NMDAR1, NR2A, NR2B, NR2C, and NR2D and a glutamate-binding protein (GBP) were not altered by kindling. These findings demonstrate that kindling induces the expression of an NMDA receptor that is novel in that it is recognized by 3H-CPP but not by 3H-CGS-19755. The molecular basis of this novel NMDA receptor is not determined by differential expression of mRNA transcripts of known NMDA receptor genes. The direction, time course, and location of the kindling-induced increase in 3H-CPP binding suggest that this novel receptor may underlie the increased sensitivity of CA3 neurons to NMDA observed in kindled animals.
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PMID:Kindling induces the long-lasting expression of a novel population of NMDA receptors in hippocampal region CA3. 802 71

The function of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is very sensitive to acute inhibition by ethanol. Because of the role of this receptor in processes such as synaptic plasticity and neuronal development, it may contribute to the acute cognitive deficits caused by ethanol, or to the deleterious effects of ethanol during gestation. Excessive stimulation of the NMDA receptor is believed to be involved in the generation of epileptiform seizure activity as well as in excitotoxic cell death. Our studies have demonstrated that there is an adaptive "up-regulation" of NMDA receptor function in brains of chronically ethanol-treated animals and in cultured cells that have been exposed chronically to ethanol. This up-regulation appears to contribute to ethanol withdrawal seizure activity, since withdrawal seizures can be attenuated by specific NMDA receptor antagonists, and the time course of the change in receptor number parallels the time course of withdrawal seizures. In addition, cells exposed chronically to ethanol are significantly more susceptible to glutamate-induced cell death, which is mediated by the NMDA receptor, indicating a key role of the NMDA receptor in the well-characterized neuronal damage that is observed after chronic ethanol exposure and withdrawal in animals and humans. Understanding the basis for withdrawal seizures and withdrawal-induced neurotoxicity provides for the development of specific and selective therapeutic agents to ameliorate these consequences of chronic ethanol exposure and withdrawal.
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PMID:The role of the NMDA receptor in ethanol withdrawal. 803 73

Increasing evidence supports the hypothesis that escalating levels of excitatory amino acids (EAAs) are responsible for neuronal cell death in a variety of acute neurological conditions including hypoxia/ischemia, trauma, seizures, and hypoglycemia. EAAs may also contribute to several chronic neurodegenerative diseases including Huntington's disease, parkinsonism, and acquired immunodeficiency syndrome dementia. A predominant form of neurotoxicity appears to be mediated by excessive activation of the N-methyl-D-aspartate subtype of glutamate receptor. This laboratory recently reported that memantine, an antiparkinsonian drug, is a potent N-methyl-D-aspartate antagonist capable of preventing the death of central neurons both in vitro and in vivo when given coincident to an EAA insult. In the present study, we found that 12 microM memantine prevented the death of neonatal rat retinal ganglion cells in primary culture when administered up to 4 hours after the initiation of N-methyl-D-aspartate receptor-mediated neurotoxicity.
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PMID:Delayed administration of memantine prevents N-methyl-D-aspartate receptor-mediated neurotoxicity. 809 95

We have studied the effect of two glutamate receptor antagonists on seizures and hippocampal neurone loss in the rat after systemic kainic acid administration. Intraperitoneal injection of the novel AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolproprionic acid) receptor antagonist NBQX (6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione) (30 mg/kg x 3 and 15 mg/kg x 3) administered 30 and 15 min. before and simultaneously with injection of kainic acid (5 mg/kg) intraperitoneally, dramatically enhanced the toxicity of kainic acid leading to death of all animals. When the NBQX dose was reduced to 8 mg/kg x 3, all animals survived and neurone damage in the hippocampus did not differ from control animals. When NBQX (30 mg/kg x 3) was administered 30- or 60 min after injection of kainic acid (8 mg/kg) intraperitoneally, no changes were observed concerning survival rates, seizure generation and neurone loss. Post-kainic acid treatment with the non-competitive NMDA receptor antagonist MK-801 (0.5 mg/kg and 1.0 mg/kg), 30 and 60 min. after intraperitoneally injection of kainic acid 8 mg/kg, abolished seizures in all animals and the neurone damage in the hippocampus was completely prevented. The results emphasize the importance of the NMDA-receptor activation for seizure generation and subsequent brain damage after intraperitoneally kainic acid. The paradoxical, unexpected effects of NBQX contrast to the protective effect of this compound after cerebral ischaemia and hypoglycaemia, conditions which are also characterized by glutamate-mediated damage. One possible explanation of the lowered seizure threshold to kainic acid after NBQX could be that NBQX is blocking AMPA receptors on interneurones more efficiently than on pyramidal cells.
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PMID:Kainic acid-induced seizures and brain damage in the rat: different effects of NMDA- and AMPA receptor antagonists. 811 8


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