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

Benzodiazepine drugs (BZ) are used for anxiety, insomnia, and seizures. They worsen memory, especially in large doses, but the mechanism of this action is uncertain. In micromolar concentrations, benzodiazepines have been shown to reduce long-term potentiation (LTP), which could be a cellular basis for their amnesic action. We have found that the LTP-inhibiting effects of BZ occur in the nanomolar concentrations attained in humans, and that this effect occurs through modulation of GABAA receptor function. We recorded extracellular synaptic input/output (I/O) curves for population spikes (PS) and EPSPs in rat hippocampal slices before and after induction of LTP. LTP increased maximal PS and EPSPs and shifted I/O curves for PS and EPSPs to the left, reflecting increased synaptic responsiveness after LTP. Curves relating EPSPs to PS were also shifted, so that after LTP larger PS were elicited for the same size EPSP (E-S potentiation). Midazolam (0.5 microM) markedly inhibited the left-shift in PS I/O curves due to E-S potentiation but did not significantly affect other parameters. 8-Phenyltheophylline (10 microM), an adenosine receptor antagonist, did not prevent midazolam inhibition of LTP. Bicuculline, a GABAA receptor antagonist, caused a dose-dependent antagonism of midazolam's LTP inhibition. Our results suggest that benzodiazepines reduce LTP primarily through reduction of E-S potentiation, and that this effect occurs through modulation of GABAA receptor function. This could in part account for the ability of benzodiazepines to disturb new memory formation.
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PMID:Midazolam inhibits long-term potentiation through modulation of GABAA receptors. 878 10

GABAergic (gamma-aminobutyric acid) transmission in the substantia nigra pars reticulata is critical for seizure control. We tested the hypothesis that there is a differential regional distribution and functionality of nigral GABAA receptor sites that is developmentally regulated. In adult rats, we determined the effects on flurothyl seizures of (Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid (ZAPA, a presumed agonist of the low-affinity GABAA receptor site), bicuculline (an antagonist of the low-affinity GABAA receptor site) and gamma-vinyl-GABA (a GABA-transaminase inhibitor), infused bilaterally in anterior or posterior substantia nigra pars reticulata. ZAPA infusions (8 micrograms) were anticonvulsant in anterior substantia nigra but proconvulsant in posterior substantia nigra. Bicuculline infusions (100 ng) were proconvulsant in anterior substantia nigra but ineffective in posterior substantia nigra. An anticonvulsant dose of gamma-vinyl-GABA, when infused in anterior substantia nigra, was proconvulsant when infused in posterior substantia nigra. In 15 day old rats, the effects of ZAPA, were biphasic: 2 micrograms was anticonvulsant while 8 micrograms was proconvulsant. There was no regional specificity. The data suggest that with maturation there is functional segregation of specific GABAA receptor subtypes involved in substantia nigra-mediated seizure control.
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PMID:Developmental regulation of regional functionality of substantial nigra GABAA receptors involved in seizures. 887 35

1. Spontaneous postsynaptic currents (PSCs) were examined in the basolateral amygdala using whole cell patch-clamp recordings in coronal slices (400 microns) from young rats (postnatal day 6-25). In most cells, Cs+ was used in the electrode to block putative voltage-activated K(+)-currents. Both inward and outward spontaneous PSCs were examined. 2. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonist, 6,7-nitroquinoxaline-2,3-dione (DNQX) blocked all inward PSCs, which reversed near 0 mV. They therefore were considered to be glutamate-mediated excitatory postsynaptic currents (EPSCs). Averaged EPSCs had a rapid 10-90% rise time (1.0 +/- 0.04 ms; mean +/- SD) and monoexponential decay (tau = 3.6 +/- 0.18 ms) at potentials negative to about -50 mV. Above this potential, a second, slower time constant (tau 1 = 41 +/- 4.5 ms at -30 mV), accounting for 10-30% of the total EPSC amplitude was resolved in 8 of 10 cells examined. The slower decay time constant was sensitive to the N-methyl-D-aspartate (NMDA)-receptor antagonist, DL-2-amino-5-phosphonovaleric acid (AP5) and therefore probably was due to activation of NMDA receptors. 3. The gamma-aminobutyric acid-A (GABAA) antagonist, bicuculline, blocked all outward PSCs, which reversed near -70 mV. They therefore were considered to be GABA-mediated inhibitory postsynaptic currents (IPSCs). Averaged IPSCs displayed rapid 10-90% rise times (1.0 +/- 0.03 ms) and monoexponential decay time constants (tau = 5.16 +/- 0.14 ms). 4. Tetrodotoxin (TTX) reduced the frequency of synaptic activity and eliminated the largest PSCs, thus reducing slightly the mean EPSC and IPSC amplitude. Most cells received bursts of spontaneous IPSCs and/or EPSCs (30-68 Hz lasting 0.5-6 s), which were also TTX sensitive. The TTX data suggest that the somata of the cells responsible for the largest PSCs and the PSC bursts were contained within the slice. 5. In addition to blocking EPSCs, DNQX blocked the bursts of IPSCs, but not all individual IPSCs. DNQX had similar effects as TTX on the bursts and frequency of the IPSCs. 6. Bicuculline enhanced spontaneous EPSC frequency (231 +/- 90%). Much of this increase was due to an increase in the bursts of EPSCs. 7. Neurons in the basolateral amygdala therefore appear to receive both excitatory (glutamatergic) and inhibitory (GABAergic) synaptic input from local neurons. The activity of the neurons responsible for these inputs are themselves largely regulated by glutamatergic and GABAergic inputs. The relevance of this local circuitry to seizures and epilepsy is discussed briefly.
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PMID:Amino acid-mediated regulation of spontaneous synaptic activity patterns in the rat basolateral amygdala. 889 Mar 6

Paired-pulse inhibition was investigated electrophysiologically in the dentate gyrus using hippocampal slices from epileptic El mice. At short interpulse intervals (IPIs), the inhibition was 30% in the El, and 90% in the control ddY mice at the ages of 10 and 15 weeks. No difference in inhibition was observed at the age of 5 weeks. Bicuculline, a GABAA receptor antagonists, attenuated the inhibition during short IPIs n the ddY mice, while in the El mice, phenobarbital and flunitrazepam, which enhance GABAA receptor function, restored the inhibitory activity comparable to that of the ddY. The disinhibition progressed with growth, closely correlating with seizure development in El mice. These results suggest that decrease in the GABAergic inhibition occurs in the dentate gyrus of the El mice with growth. GABA concentration in the hippocampus was also quantified using HPLC. In El mice, GABA level was significantly lower than that in ddY mice at the ages of 5 and 15 weeks. Thus, the disinhibition observed in the El dentate gyrus at 15 weeks of age does not appear to be directly related to the content of GABA. GABAergic disinhibition suggests possible loss of unknown inhibition control factor(s) in the El dentate gyrus as growth progresses. The growth-dependent disinhibition in the granule cells may be prerequisite for epileptogenesis in El mice.
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PMID:Granule cell disinhibition in dentate gyrus of genetically seizure susceptible El mice. 903 6

Slice in vitro preparations have been useful to study the cellular basis of some epilepsy related phenomena. However, the cellular mechanisms that generate ictal activity remain poorly understood. Therefore, an experimental in vitro model capable of generating seizure-like activity might contribute to the study of the cellular basis of seizures. The outstanding resistance to hypoxia of turtles enabled us to develop an in vitro preparation that keeps all the cortical neural circuitry intact. A whole cerebral hemisphere of the turtle Chrysemys d'orbigny was isolated (n = 45) and simultaneous electrographic and intracellular recordings were performed in the medial cortex. The electrographic activity was composed by a non-rhythmic, low-voltage (10-20 microV) activity interrupted by spontaneous large (50-700 microV) sharp waves (LSWs). The cellular counterpart of the LSWs was often a burst of action potentials that resembled the paroxysmal depolarisation shift (PDS). Bicuculline (20-40 microM, n = 20) increased the interictal-like activity and in some preparations (3 out of 20) provoked seizure-like events. Complex bursting activity and a slow afterhyperpolarisation were cellular events observed during seizures. We propose that this model might be a valuable tool for the study the cellular mechanisms involved in the transition from the interictal to the ictal activities.
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PMID:The cerebral hemisphere of the turtle in vitro. An experimental model with spontaneous interictal-like spikes for the study of epilepsy. 925 97

PNU-151774E [(S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino) propanamide, methanesulfonate] is a structurally novel anticonvulsant having Na+ channel-blocking and glutamate release-inhibiting properties, as well as being a MAOB inhibitor. Its anticonvulsant activity was evaluated in the maximal electroshock (MES) test and in chemically induced seizures (bicuculline, BIC; picrotoxin, PIC; 3-mercaptopropionic acid, 3-MPA; pentylenetetrazole, PTZ; strychnine, STRYC). Behavioral toxicity was evaluated in the rotorod test with measurements of spontaneous locomotor activity and passive avoidance responding. The anti-MES activity of PNU-151774E in both mice and rats, respectively, produced ED50 values of 4.1 mg/kg and 6.9 mg/kg after i.p. administration or 8.0 mg/kg and 11.8 mg/kg after p.o. administration. Oral anti-MES activity in rats peaked between 1 and 2 h after administration and was evident up to 4 h. This activity was related to brain levels of unchanged drug which peaked at 37 mM within 1 h. Oral ED50 values (mg/kg) effective in blocking tonic extension seizures by chemical convulsants in mice were: BIC (26.9), PIC (60.6), 3-MPA (21.5), STRYC (104.1) and PTZ (26.8). This potency was associated with high therapeutic indices relative to: MES (78.2), BIC (23.3), PIC (10.3), 3-MPA (29.1) and STRYC (6.0). No evidence of tolerance to anti-MES activity after repeated dosing was observed. PNU-151774E did not show anti-absence seizure activity as assessed by i.v. infusion of PTZ. PNU-151774E impaired spontaneous activity in rats only at the oral rotorod ED50 dose of 700 mg/kg p.o. PNU-151774E did not impair passive avoidance responding at doses up to 40 times the oral MES ED50 dose in rats. These results indicate that PNU-151774E is an anticonvulsant effective in various seizure models with a wide therapeutic window, and with a low potential to induce tolerance and locomotor or cognitive side effects.
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PMID:Preclinical evaluation of PNU-151774E as a novel anticonvulsant. 958 May 76

El mouse has been found to be characteristics with hippocampal disinhibition, and has been suggested decrease in GABAergic synaptic transmission [Ono et al., Brain Res. 745 (1997) 165-172; Fueta et al. , Brain Res. 779 (1998) 324-328]. The efficacy of GABAergic synapses can be modulated in response to trains of low frequency stimulation. The frequency potentiation of a population spike (PS) and the field excitatory postsynaptic potential (fEPSP) induced by a low frequency stimulation (2 Hz for 15 s) were recorded for the CA3 subfield, and PS alone for the CA1 subfield and dentate gyrus. PS frequency potentiation was greater in El mice than in non-epileptic control ddY mice. Especially the CA3 subfield exhibited a high PS frequency potentiation (300+/-73%) compared to age-matched ddY mice (64+/-24%). However, EPSP frequency potentiation was similar in El and ddY mice. The degree of PS frequency potentiation in CA3 was decreased by the reduction of extracellular Ca2+ from 2 to 1 mM in both strains, suggesting presynaptic involvement. The potentiation in El mice was suppressed by AMPA/kainate type receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dion (CNQX), but more than half of the control value remained at 5 microM, whereas the potentiation in ddY mice was abolished at this concentration. N-methyl-d-aspartate (NMDA) type receptor antagonist 3-3 (2-carboxypiperazine-4-yl) propyl-1-phosphonate (10 microM; CPP) did not affect the potentiation. Bicuculline (5 microM), GABAA receptor antagonist, did not increase the amplitude of PS during stimulation but induced epileptic (multiple PSs) potentials. High PS frequency potentiation of El mice was mimicked to the degree of that in ddY mice by a low dose of GABAB receptor agonist baclofen (3 microM). The suppression by baclofen was partially reversed by the antagonist saclofen (500 microM). The large frequency potentiation in young El mice, which do not have seizure-susceptibility, indicates an intrinsic property in El mice. It is suggested that the high synchronization of CA3 neurons in El mice is due to a little activation of GABAB receptor activation and also to enhancement of non-NMDA type synaptic transmission.
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PMID:Large frequency potentiation induced by 2 Hz stimulation in the hippocampus of epileptic El mice. 959 33

Pilocarpine, a muscarinic agonist, produces status epilepticus that is associated with the later development of chronic recurrent seizures. When applied to rat hippocampal slices, pilocarpine (10 microM) produced brief (<200 ms) epileptiform discharges that resembled interictal activity that occurs between seizures, as well as more prolonged synchronous neuronal activation that lasted seconds (3-20 s), and was comparable to ictal or seizures-like discharges. We assessed the factors that favored ictal patterns of activity and determined the biophysical properties of the ictal discharge. The probability of observing ictal discharges was increased when extracellular potassium ([K+]o) was increased from 5 to 7.5 mM. Raising [K+]o to 10 mM resulted in loss of ictal patterns and, in 20 of 34 slices, desynchronization of epileptiform activity. Making the artificial cerebrospinal fluid (ACSF) hyposmotic favored ictal discharges at 5 mM [K+]o, but shifted 7.5 mM [K+]o ACSF patterns to interictal discharges or desynchronized activity. Conversely, increasing osmolality suppressed ictal patterns. The pilocarpine-induced ictal discharges were blocked by atropine (1 microM, n = 5), a muscarinic antagonist, and pirenzepine (1 microM, n = 6), a selective M1 receptor antagonist. Kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor blockade stopped all epileptiform activity (n = 8). The N-methyl--aspartate antagonist ,-2-amino-5-phosphonovaleric acid (100 microM, n = 34) did not change the pattern of epileptiform activity but significantly increased the rate of interictal discharges and prolonged the duration of ictal discharges. The ictal discharge was characterized intracellularly by a depolarization that was associated with action potential generation and persisted as a membrane oscillation of 4-10 Hz. The ictal oscillations reversed in polarity at -22.7 +/- 2.2 mV (n = 11) with current-clamp recordings and -20.9 +/- 3.1 mV (n = 7) with voltage-clamp recordings. The reversal potential of the ictal discharge in the presence of the gamma-aminobutyric acid-A blocker bicuculline (10 microM, n = 6) was -2.2 +/- 2.6 mV and was significantly different from that measured without bicuculline. Bicuculline added to 7.5 mM [K+]o and 10 microM pilocarpine did not cause epileptiform activity to change pattern but significantly increased the rate of interictal discharges and prolonged the ictal discharge duration. Both synaptic and nonsynaptic mechanisms are important for the generation of ictal patterns of epileptiform activity. Although the synchronous epileptiform activity produced by pilocarpine required fast glutamate-mediated synaptic transmission, the transition from an interictal to ictal pattern of activity depended on [K+]o and could be influenced by extracellular space.
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PMID:Ictal epileptiform activity in the CA3 region of hippocampal slices produced by pilocarpine. 963 5

The purpose of this study was to evaluate the effects of the new anticonvulsant drug N-(2-amino-4-[fluorobenzylaminol-phenyl) carbamic acid ethyl ester (retigabine, D-23129, ASTA Medica, Dresden, Germany) on different patterns of epileptiform activity induced by 4-aminopyridine (4AP) in rat entorhinal cortex hippocampal slices. Application of 4AP (100 microM) induced in entorhinal cortex two different types of epileptiform activities; seizure-like events (SLE) and interictal epileptiform discharges (IED). Bicuculline (10 microM) changed 4AP-induced SLE and IED to recurrent epileptiform discharges (RED). IED were isolated after blockade of the SLE by glutamate receptor antagonists for alpha-amino-3-hydroxy-5-methylisoxazole4-proprionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors, i.e. 1,2,3,4 tetrahydro-6-nitro-2,3-dioxo-benzolflquinoxaline-7-sulfonamide (NBQX, 10 microM) and 2-amino-5-phosphonovaleric acid (APV, 30 microM). Anticonvulsant properties of retigabine were evaluated as effect on the frequency and amplitude of SLE, IED and RED. Retigabine suppressed all types of epileptiform events in a dose dependent and reversible manner. SLE were suppressed in 71.4 and 100% of slices by 5 and 10 microM, respectively. The frequency of IED was significantly reduced by 20 microM retigabine (40.9+/-24.5%) and IED were blocked completely by 50 microM retigabine. When IED were isolated by application of glutamate antagonists 20 microM retigabine was sufficient to block this activity completely. RED induced by combined application of bicuculline and 4AP were blocked in 71.4% of the tested slices with 100 microM retigabine. The frequency of the RED in the remaining slices was reduced by 96.1+/-6.1%. We conclude that retigabine acts on a large variety of different epileptiform activities in temporal lobe structures that are known to develop readily pharmacoresistant seizures.
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PMID:Effects of retigabine (D-23129) on different patterns of epileptiform activity induced by 4-aminopyridine in rat entorhinal cortex hippocampal slices. 993 48

The effects of drugs affecting GABA and glutamic acid receptors on theophylline-induced seizures were investigated in mice. Theophylline elicited tonic seizures in mice in a dose dependent manner. Muscimol, DABA and AOAA significantly prolonged the onset and significantly decreased the incidence of theophylline-induced seizures. Baclofen significantly delayed the onset of the tonic seizures induced by theophylline. Bicuculline and picrotoxin significantly shortened the onset and significantly increased the incidence of seizures induced by a low dose of theophylline and also significantly antagonized muscimol-attenuating effect against theophylline seizures. N-methyl-DL-aspartic acid significantly shortened the onset and significantly increased the incidence of seizures elicited by a low dose of theophylline. D-(-)-2-amino-phosphonopentanoic acid effectively delayed the onset and significantly decreased the incidence of seizures elicited by theophylline and also significantly antagonized the potentiating effect of N-methyl-DL-aspartic acid on seizures induced by a low dose of theophylline. Dextromethorphan and ketamine profoundly shortened the onset of theophylline-induced seizures. Clonidine effectively prolonged the onset and significantly decreased the incidence of theophylline-induced seizures. These data indicate that GABA(A) and N-methyl-D-aspartic acid receptors may mediate theophylline-elicited tonic seizures in mice.
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PMID:Gamma-aminobutyric acid and glutamic acid receptors may mediate theophylline-induced seizures in mice. 1021 93


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