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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of kainate (KA)-induced epileptic seizures on the binding properties of hippocampal glutamate receptors, on the modulation of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/quisqualate receptor by phospholipase A2 (PLA2), and on the formation of long-term potentiation (LTP) were studied in hippocampal membranes and hippocampal slices. Systemic administration of KA (10 mg/kg; 15 hr survival) produced specific changes in the binding properties of the AMPA/quisqualate receptors and its regulation. Whereas the binding of various ligands to the N-methyl-D-aspartate receptors was not modified by KA treatment, there was a significant decrease in the maximal number of binding sites for [3H]AMPA. In addition, the increase in [3H]AMPA binding elicited by PLA2 treatment of hippocampal, but not cerebellar, membranes was markedly decreased after KA injection. LTP was also substantially reduced in area CA1 of hippocampal slices from KA-treated animals. The loss of LTP was not due to changes in postsynaptic responses elicited by the bursts that trigger the potentiation effect, thus suggesting that KA treatment disrupts processes that follow N-methyl-D-aspartate receptor activation. Systemic administration of KA was associated with calpain activation as the amount of spectrin breakdown products was increased severalfold in hippocampus but not in cerebellum. Pretreatment of telencephalic membranes with calpain greatly reduced the PLA2-induced increase in [3H]AMPA binding. The results provide evidence in favor of an essential role of PLA2 in the development of LTP and suggest that the order of activation of different calcium-dependent processes is critical for producing the final changes underlying LTP.
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PMID:Modulation of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/quisqualate receptors by phospholipase A2: a necessary step in long-term potentiation? 184 14

The calcium-dependent gamma-aminobutyric acid (GABA) and glutamate release from rat hippocampal CA1 slices, evoked by a 1-min depolarization with 50 mM K+, was investigated in different stages of kindling epileptogenesis. Kindling was induced by tetanic stimulation of the Schaffer collateral/commissural pathway. In agreement with our previous results, we found a significantly increased calcium-dependent GABA release compared to that of implanted controls, in a group of fully kindled animals 1 day after the last seizure and also 25-36 days after the last seizure. In addition, we found that the increase in GABA release was associated with late phases of kindling epileptogenesis since no significant alterations were found in partly kindled animals that had received only 6 kindling stimulations while a significant increase was apparent in animals that had received 14 tetanic stimuli. When the release protocol was carried out in the presence of SK&F 89776-A, a blocker of the GABA uptake carrier, an additional amount of GABA was found after depolarization. This additional amount of GABA, reflecting the amount of GABA taken up under conditions without blocker, was in kindled animals not different from controls which demonstrates that a reduced GABA uptake does not account for the observed enhanced release in kindled animals. The calcium-dependent release of glutamate evoked by 1 min of high potassium depolarization was not significantly changed in the kindled groups. Only after prolonged depolarization during 4 subsequent minutes a significant increase in animals of the fully kindled group and at long-term after kindling was observed. The threshold K+ concentration for eliciting a calcium-dependent release of GABA and glutamate, was not changed in the kindled animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Development of changes in endogenous GABA release during kindling epileptogenesis in rat hippocampus. 186 54

Experiments were carried out to test whether changes in the sensitivity of hippocampal pyramidal neurons to the neurotransmitters glutamate, GABA and noradrenaline may be associated with the establishment of an epileptogenic focus induced by kindling. The effects of iontophoretically applied neurotransmitters on the firing rate of single units were quantified in the rat hippocampal CA1 area in kindled and control animals. Kindling was induced by electrical tetanic stimulation of the Schaffer collateral/commissural fibers. Firing was evoked by local glutamate iontophoresis while simultaneous GABA or noradrenaline application suppressed this response. A significant reduction of the GABAergic inhibitory action on the firing rate in kindled animals studied around four or around 42 days after the last convulsion was found. In the same neurons, the suppressive effect of noradrenaline was not different from controls. The neurons of kindled animals, investigated around four days after the last seizure, had a reduced sensitivity for glutamate; more glutamate ejection current was needed to evoke firing or to evoke the maximum firing rate. In contrast, the responsiveness for glutamate was significantly increased long-term after the last convulsion. These findings demonstrate that hippocampal Schaffer collateral kindling is associated with a long-lasting reduced effectiveness of the GABA-mediated response on glutamate-evoked firing in CA1.
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PMID:A long-lasting decrease in the inhibitory effect of GABA on glutamate responses of hippocampal pyramidal neurons induced by kindling epileptogenesis. 187 Jun 98

1. The pharmacological properties of the benzodiazepine receptor ligand, FG 8205 (7-chloro-5,6-dihydro-5-methyl-6-oxo-3-(5-isopropyl-1,2,4-oxadiazol++ +-3-yl)-4H- imidazol[1,5a][1,4]benzodiazepine) have been examined. 2. FG 8205 potently displaced [3H]-flumazenil binding in rat cortical membranes with a Ki of 3.3 nM, but was inactive at 13 neurotransmitter recognition sites. 3. Consistent with a partial agonist profile, the affinity of FG 8205 for the benzodiazepine recognition site was increased in the presence of gamma-aminobutyric acid (GABA, 300 microM) by a degree (-log [IC50 in the presence of GABA/IC50 alone] = 0.34) significantly less than found for diazepam (0.46). FG 8205 also potentiated the inhibitory potency of the GABAA-receptor agonist, isoguvacine, on the hippocampal CA1 population spike and, again, the maximum shift (-log dose-ratio = 0.2) was significantly less than that seen with diazepam (0.4). 4. In anticonvulsant studies, the ED50 doses of FG 8205 and diazepam needed to antagonize seizures induced by pentylenetetrazol (PTZ) or by sound in audiogenic seizure prone mice were similar with values of 0.2-0.3 mg kg-1, i.p. However, even high doses of FG 8205 (50 mg kg-1) did not protect against seizures induced by electroshock. 5. FG 8205 released responding suppressed by footshock in a rat operant conditioned emotional response task over the dose range 0.5-50 mg kg-1 (i.p.). Similar doses of FG 8205 had a marked taming effect in cynomolgus monkeys. However, measures of sedation and ataxia (as measured by rotarod in the mouse, climbing behaviour in the rat, and by scoring arousal and co-ordination in primates) were slight and only transiently affected by FG 8205, and FG 8205 significantly antagonized the rotarod performance deficit induced by diazepam in the mouse. 6. While the potentiation by FG 8205 of the response to isoguvacine in the rat hippocampal slice and the anxiolytic-like effects of the compound in both rats and primates were reversed by the benzodiazepine receptor antagonist, flumazenil, high doses of the antagonist were able only marginally to block the protective effects of FG 8205 against seizures induced by PTZ in the mouse. 7. Thus, FG 8205 does not show the marked motor impairment characteristic of full agonists at the benzodiazepine receptor, consistent with its partial agonist profile in in vitro assay systems. Nevertheless, the compound has sufficient intrinsic activity to maintain high efficacy in anticonvulsant and anxiolytic tests.
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PMID:The pharmacological properties of the imidazobenzodiazepine, FG 8205, a novel partial agonist at the benzodiazepine receptor. 196 8

1. The pharmacological properties of CGP 37849 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid; 4-methyl-APPA) and its carboxyethylester, CGP 39551, novel unsaturated analogues of the N-methyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonopentanoate (AP5), were evaluated in rodent brain in vitro and in vivo. 2. Radioligand binding experiments demonstrated that CGP 37849 potently (Ki 220 nM) and competitively inhibited NMDA-sensitive L-[3H]-glutamate binding to postsynaptic density (PSD) fractions from rat brain. It inhibited the binding of the selective NMDA receptor antagonist, [3H]-((+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), with a Ki of 35 nM, and was 4, 5 and 7 fold more potent than the antagonists [+/-)-cis-4-phosphonomethylpiperidine-2-carboxylic acid) (CGS 19755), CPP and D-AP5, respectively. Inhibitory activity was associated exclusively with the trans configuration of the APPA molecule and with the D-stereoisomer. CGP 39551 showed weaker activity at NMDA receptor recognition sites and both compounds were weak or inactive at 18 other receptor binding sites. 3. CGP 37849 and CGP 39551 were inactive as inhibitors of L-[3H]-glutamate uptake into rat brain synaptosomes and had no effect on the release of endogenous glutamate from rat hippocampal slices evoked by electrical field stimulation. 4. In the hippocampal slice in vitro, CGP 37849 selectively and reversibly antagonized NMDA-evoked increases in CA1 pyramidal cell firing rate. In slices bathed in medium containing low Mg2+ levels, concentrations of CGP 37849 up to 10 microM suppressed burst firing evoked in CAl neurones by stimulation of Schaffer collateral-commissural fibres without affecting the magnitude of the initial population spike; CGP 39551 exerted the same effect but was weaker. In vivo, oral administration to rats of either CGP 37849 or CGP 39551 selectively blocked firing in hippocampal neurones induced by ionophoreticallyapplied NMDA, without affecting the responses to quisqualate or kainate. 5. CGP 37849 and CGP 39551 suppressed maximal electroshock-induced seizures in mice with ED50 s of 21 and 4 mg kg'- p.o., respectively. 6. CGP 37849 and CGP 39551 are potent and competitive NMDA receptor antagonists which show significant central effects following oral administration to animals. As such, they may find value as tools to elucidate the roles of NMDA receptors in brain function, and potentially as therapeutic agents for the treatment of neurological disorders such as epilepsy and ischaemic brain damage in man.
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PMID:CGP 37849 and CGP 39551: novel and potent competitive N-methyl-D-aspartate receptor antagonists with oral activity. 197 95

The intracarotid amobarbital sodium (Amytal) procedure (IAP) was performed for 46 patients with temporal lobe epilepsy (21 with left seizure foci; 25 with right seizure foci). After anteromedial temporal lobectomy, neuronal densities were established for hippocampal subfields CA1, CA2, and CA3; the hilum; and the dentate granule cell layer. Intracarotid amobarbital procedure memory results were related to CA3 neuronal loss only. Patients who did not demonstrate memory after injection contralateral to the seizure focus had significantly fewer cells in CA3 than patients who did. Additionally, a significant correlation was observed between the intracarotid amobarbital procedure memory examination raw score after injection contralateral to the seizure focus and CA3 cell density. Using chi 2 analysis, significant differences were documented in the frequency with which memory was demonstrated after injection contralateral to the seizure focus for groups of patients classified by degree of CA3 neuronal loss. This finding supports prior research showing subfield specificity in some memory processes.
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PMID:The neural substrate of memory impairment demonstrated by the intracarotid amobarbital procedure. 198 26

A quantitative autoradiographic study was made on the binding of the phosphatidylinositol system ligand [3H]inositol(1,4,5)-trisphosphate (IP3) to forebrain sections from rats decapitated various times after 10 min of forebrain ischemia. To investigate the effect of a deafferentation of the hippocampal CA1, kainic acid-induced CA3-lesioned rats with or without 10 min of cerebral ischemia, were also included. The highest binding was found in the hippocampal CA1. Ten min of cerebral ischemia did not change the binding significantly. Between 5 min and 1 h of recirculation there was a 25-35% binding decline in all regions. In the CA1, where the pyramidal cells became necrotic 6 days after ischemia, there was a further decline to 16% of control. In the cortex, where there is no necrosis in this model, binding did not return to control values until day 14. Four days after a selective CA3 lesion with kainic acid, there was a significant 25% decline in the cortex, dentate gyrus and CA1, whereas in the necrotic CA3 binding declined to 54% of control. Ten min of ischemia did not alter this binding significantly. This decrease in calcium mobilizing intracellular receptors after ischemia and seizures could be due to increased membrane degradation, or to a more specific down-regulation following increased intracellular concentration of calcium and IP3.
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PMID:Modification of [3H]inositoltrisphosphate binding in kainic acid-lesioned and postischemic rat hippocampus. 201 67

In rats poisoned with soman (s.c. 100 micrograms/kg), a potent inhibitor of cholinesterase (ChE), the numbers of dendritic spines of Golgi impregnated hippocampal pyramidal cells (CA1 sector) were evaluated within the first hour of the intoxication. Animals that experienced convulsions showed a rapid and striking decrease in the density of dendritic spines which could be reduced by nearly 80% of the controls in the basal dendrites 60 min post-soman exposure. Although the exact mechanisms cannot be determined from the present study, it is suggested that the spine loss may represent: (1) the first sign of the seizure-related neuronal changes which are known to occur later during soman intoxication; and (2) the expression of the 'dendrotoxic' effects produced by certain non-cholinergic excitatory transmitters such as glutamate.
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PMID:Early dendritic changes in hippocampal pyramidal neurones (field CA1) of rats subjected to acute soman intoxication: a light microscopic study. 205 43

Limbic seizure status was induced by microinjection of kainic acid into a unilateral amygdala in rats. Two hours after kainic acid injection, distant neuronal cell damage was produced, especially in the hippocampal CA3 on the kainic acid-injected side. In order to elucidate the mechanism of this neuronal cell damage, local cerebral glucose utilization and local cerebral blood flow were studied by means of an autoradiographic method using [14C]2-deoxyglucose and [14C]iodoantipyrine during kainic acid-induced limbic seizure status. These studies were performed 2 h after kainic acid microinjection into a unilateral amygdala. Both local cerebral glucose utilization and local cerebral blood flow were remarkably increased in the limbic system, ventrobasal complex of the thalamus, septal nucleus, nucleus accumbens, caudate nucleus, substantia nigra and hypothalamus on the kainic acid-injected side. In the hippocampus, local cerebral glucose utilization increased 2.6 times control in CA1 and 4.1 times in CA3, whereas the rates of increase in local cerebral blood flow were similarly low in CA1 and CA3: 1.2 and 1.4 times control, respectively. The results demonstrated that the degree of uncoupling of local cerebral glucose utilization and local cerebral blood flow were higher in CA3 than in CA1, and also suggested that relative hypoxia occurred in CA3 in this high degree of uncoupling, resulting in pyramidal cell damage in CA3 in kainic acid-induced limbic seizure status.
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PMID:Uncoupling of local blood flow and metabolism in the hippocampal CA3 in kainic acid-induced limbic seizure status. 212 Jun 14

Induction of messenger RNA encoding the 70-kDa heat shock or stress protein, hsp70, and the product of the proto-oncogene c-fos was evaluated in gerbil hippocampus by in situ hybridization at various recirculation intervals after 5 minutes of ischemia. Striking increases in c-fos RNA were observed in dentate granule cells within 15 minutes of recirculation and remained evident through 1 hour, returning to undetectable control levels by 3 hours. Modest c-fos hybridization was seen in CA1 and CA3 neurons during the same time course. These results are consistent with the rapid and transient stimulation-induced c-fos expression observed in many experimental systems. Hsp70 expression showed a longer time course, being strongly induced in all major hippocampal neuron populations within 3 hours and persisting for approximately 12 hours in dentate granule cells and through 24 hours in CA3 pyramidal neurons. Notably, the most prolonged expression of hsp70 RNA was observed in vulnerable CA1 neurons that minimally accumulate the immunoreactive protein, with hybridization detected essentially until the death of this cell population at 3-4 days. These studies demonstrate an overlapping distribution of hsp70 and c-fos expression in gerbil hippocampus after ischemia, although there are differences in time course and in the relative induction observed in different neuron populations. The transient increase in c-fos hybridization in dentate granule cells is identical to that seen in various seizure paradigms and provides further support for activation of hippocampal circuitry after ischemia. The prolonged time course of hsp70 messenger RNA expression in vulnerable CA1 neurons may provide a molecular correlate of proposed excitotoxic mechanisms mediating delayed neuronal death.
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PMID:70-kDa heat shock protein and c-fos gene expression after transient ischemia. 212 54


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