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Epileptiform Burst (epileptiform + burst)
Selected AbstractsInterneuron subtype specific activation of mGluR1/5 during epileptiform activity in hippocampusEPILEPSIA, Issue 8 2010Nathalie T Sanon Summary Purpose:, Specific inhibitory interneurons in area CA1 of the hippocampus, notably those located in stratum oriens,alveus (O/A-INs), are selectively vulnerable in patients and animal models of temporal lobe epilepsy (TLE). The excitotoxic mechanisms underlying the selective vulnerability of interneurons have not been identified but could involve group I metabotropic glutamate receptor subtypes (mGluR1/5), which have generally proconvulsive actions and activate prominent cationic currents and calcium responses specifically in O/A-INs. Methods:, In this study, we examine the role of mGluR1/5 in interneurons during epileptiform activity using whole-cell recordings from CA1 O/A-INs and selective antagonists of mGluR1, (LY367385) and mGluR5 (MPEP) in a disinhibited rat hippocampal slice model of epileptiform activity. Results:, Our data indicate more prominent epileptiform burst discharges and paroxysmal depolarizations (PDs) in O/A-INs than in interneurons located at the border of strata radiatum and lacunosum/moleculare (R/LM-INs). In addition, mGluR1 and mGluR5 significantly contributed to epileptiform responses in O/A-INs but not in R/LM-INs. Epileptiform burst discharges in O/A-INs were partly dependent on mGluR5. PDs and associated postsynaptic currents were dependent on both mGluR1, and mGluR5. These receptors contributed differently to postsynaptic currents underlying PDs, with mGluR5 contributing to the fast and slow components and mGluR1, to the slow component. Discussion:, These findings support interneuron subtype-specific activation and differential contributions of mGluR1, and mGluR5 to epileptiform activity in O/A-INs, which could be important for their selective vulnerability in TLE. [source] Low Concentration of DL-2-Amino-5-phosphonovalerate Induces Epileptiform Activity in Guinea Pig Hippocampal SlicesEPILEPSIA, Issue 10 2001Ali Gorji Summary: , Purpose: The specific mechanisms by which low concentrations of cyclosporine induce seizures and low concentrations of phencyclidine provoke behavioral excitation remain to be elucidated. Both compounds block N -methyl- d -aspartate (NMDA) receptors. The aim of this study was to determine if low concentrations of the NMDA-receptor blockers increase the seizure susceptibility. Methods: Guinea pig hippocampal slices were exposed to artificial cerebrospinal fluid containing the NMDA blocker dl -2-amino-5-phosphono-valerate (APV; 0.1,10 ,M). Extracellular field potentials were recorded from CA1 and CA3 regions. Results: Low concentrations of APV induced epileptiform burst discharges (0.1,0.25 ,M), whereas higher doses failed to decrease the seizure threshold (1,10 ,M). Conclusions: The results indicate that the excitatory effect of low concentrations NMDA blockers may play a role in the neurotoxicity of aforementioned substances. [source] Pharmacological profile of essential oils derived from Lavandula angustifolia and Melissa officinalis with anti-agitation properties: focus on ligand-gated channelsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2008Liping Huang Both Melissa officinalis (Mo) and Lavandula angustifolia (La) essential oils have putative anti-agitation properties in humans, indicating common components with a depressant action in the central nervous system. A dual radioligand binding and electrophysiological study, focusing on a range of ligand-gated ion channels, was performed with a chemically validated essential oil derived from La, which has shown clinical benefit in treating agitation. La inhibited [35S] TBPS binding to the rat forebrain gamma aminobutyric acid (GABA)A receptor channel (apparent IC50 = 0.040 ± 0.001 mg mL,1), but had no effect on N -methyl- d -aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or nicotinic acetylcholine receptors. A 50:50 mixture of Mo and La essential oils inhibited [3H] flunitrazepam binding, whereas the individual oils had no significant effect. Electrophysiological analyses with rat cortical primary cultures demonstrated that La reversibly inhibited GABA-induced currents in a concentration-dependent manner (0.01,1 mg mL,1), whereas no inhibition of NMDA- or AMPA-induced currents was noted. La elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission, with a net depressant effect on neurotransmission (in contrast to the classic GABAA antagonist picrotoxin which evoked profound epileptiform burst firing in these cells). These properties are similar to those recently reported for Mo. The anti-agitation effects in patients and the depressant effects of La we report in neural membranes in-vitro are unlikely to reflect a sedative interaction with any of the ionotropic receptors examined here. These data suggest that components common to the two oils are worthy of focus to identify the actives underlying the neuronal depressant and anti-agitation activities reported. [source] Pharmacological profile of an essential oil derived from Melissa officinalis with anti-agitation properties: focus on ligand-gated channelsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2008Sawsan Abuhamdah A dual radioligand binding and electrophysiological study, focusing on a range of ligand-gated ion channels, was performed with a chemically-validated essential oil derived from Melissa officinalis (MO), which has shown clinical benefit in treating agitation. MO inhibited binding of [35S] t -butylbicyclophosphorothionate (TBPS) to the rat forebrain gamma-aminobutyric acid (GABA)A receptor channel (apparent IC50 0.040±0.001 mg mL,1), but had no effect on N -methyl- d -aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropianate (AMPA) or nicotinic acetylcholine receptors. Electrophysiological analyses with primary cultures of rat cortical neurons demonstrated that MO reversibly inhibited GABA-induced currents in a concentration-dependent manner (0.01,1 mg mL,1), whereas no inhibition of NMDA- or AMPA-induced currents was noted. Interestingly, MO elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission, with a net depressant effect on neurotransmission (in contrast to the classical GABAA antagonist picrotoxinin which evoked profound epileptiform burst firing in these cells). The anti-agitation effects in patients and the depressant effects of MO in in-vitro we report in neural membranes are unlikely to reflect a sedative interaction with any of the ionotropic receptors examined here. [source] Cooling Abolishes Neuronal Network Synchronization in Rat Hippocampal SlicesEPILEPSIA, Issue 6 2002Sam P. Javedan Summary: ,Purpose: We sought to determine whether cooling brain tissue from 34 to 21°C could abolish tetany-induced neuronal network synchronization (gamma oscillations) without blocking normal synaptic transmission. Methods: Intracellular and extracellular electrodes recorded activity in transverse hippocampal slices (450,500 ,m) from Sprague,Dawley male rats, maintained in an air,fluid interface chamber. Gamma oscillations were evoked by afferent stimulation at 100 Hz for 200 ms. Baseline temperature in the recording chamber was 34°C, reduced to 21°C within 20 min. Results: Suprathreshold tetanic stimuli evoked membrane potential oscillations in the 40-Hz frequency range (n = 21). Gamma oscillations induced by tetanic stimulation were blocked by bicuculline, a ,-aminobutyric acid (GABA)A -receptor antagonist. Cooling from 34 to 21°C reversibly abolished gamma oscillations in all slices tested. Short, low-frequency discharges persisted after cooling in six of 14 slices. Single-pulse,evoked potentials, however, were preserved after cooling in all cases. Latency between stimulus and onset of gamma oscillation was increased with cooling. Frequency of oscillation was correlated with chamber cooling temperature (r = 0.77). Tetanic stimulation at high intensity elicited not only gamma oscillation, but also epileptiform bursts. Cooling dramatically attenuated gamma oscillation and abolished epileptiform bursts in a reversible manner. Conclusions: Tetany-induced neuronal network synchronization by GABAA -sensitive gamma oscillations is abolished reversibly by cooling to temperatures that do not block excitatory synaptic transmission. Cooling also suppresses transition from gamma oscillation to ictal bursting at higher stimulus intensities. These findings suggest that cooling may disrupt network synchrony necessary for epileptiform activity. [source] Carbonic Anhydrase Inhibitor Sulthiame Reduces Intracellular pH and Epileptiform Activity of Hippocampal CA3 NeuronsEPILEPSIA, Issue 5 2002Tobias Leniger Summary: ,Purpose: Sulthiame is a carbonic anhydrase (CA) inhibitor with an anticonvulsant effect in the treatment of benign and symptomatic focal epilepsy in children. The aim of the study was to elucidate the mode of action of sulthiame with respect to possible changes of intracellular pH (pHi) that might develop along with sulthiame's anticonvulsant properties. Methods: The effects of sulthiame (a) on pHi of 2,,7-bis(2-carboxyethyl)-5(6)-carboxyfluorescein-acetoxymetyl ester (BCECF-AM) loaded CA3 neurones as well as (b) on epileptiform activity (induced by 50 ,M 4-aminopyridine) were compared with those of the CA inhibitors acetazolamide and benzolamide. Results: In the majority of neurons, sulthiame (1.0,1.5 mM; n = 8) as well as the membrane permeant acetazolamide (0.5,1.0 mM; n = 6) reversibly decreased pHi by 0.18 ± 0.05 (SD) and 0.17 ± 0.10 (SD) pH units, respectively, within 10 min. The poor membrane permeant benzolamide (1.0,2.0 mM) had no influence on pHi (n = 8). Sulthiame (1.0,2.5 mM) and acetazolamide (1.0,2.0 mM) reversibly reduced the frequency of action potentials and epileptiform bursts after 10,15 min (n = 9, n = 7), whereas benzolamide (1.0,2.0 mM) had no effect (n = 6). Conclusions: The results suggest that sulthiame acts as a membrane-permeant CA inhibitor whose beneficial effect on epileptiform activity results at least in part from a modest intracellular acidosis of central neurons. [source] A Possible Role for Gap Junctions in Generation of Very Fast EEG Oscillations Preceding the Onset of, and Perhaps Initiating, SeizuresEPILEPSIA, Issue 2 2001Roger D. Traub Summary: ,Purpose: We propose an experimentally and clinically testable hypothesis, concerning the origin of very fast (>,70 Hz) EEG oscillations that sometimes precede the onset of focal seizures. These oscillations are important, as they may play a causal role in the initiation of seizures. Methods: Subdural EEG recordings were obtained from children with focal cortical dysplasias and intractable seizures. Intra- and extracellular recordings were performed in rat hippocampal slices, with induction of population activity, as follows: (a) bath-applied tetramethylamine (an intracellular alkalinizing agent, that opens gap junctions); (b) bath-applied carbachol, a cholinergic agonist; and (c) focal pressure ejection of hypertonic K+ solution. Detailed network simulations were performed, the better to understand the cellular mechanisms underlying oscillations. A major feature of the simulations was inclusion of axon,axon gap junctions between principal neurons, as supported by recent experimental data. Results: Very fast oscillations were found in children before seizure onset, but also superimposed on bursts during the seizure, and on interictal bursts. In slice experiments, very fast oscillations had previously been seen on interictal-like bursts; we now show such oscillations before, between, and after epileptiform bursts. Very fast oscillations were also seen superimposed on gamma (30,70 Hz) oscillations induced by carbachol or hypertonic K+, and in the latter case, very fast oscillations became continuous when chemical synapses were blocked. Simulations replicate these data, when axonal gap junctions are included. Conclusions: Electrical coupling between principal neurons, perhaps via axonal gap junctions, could underlie very fast population oscillations, in seizure-prone brain, but possibly also in normal brain. The anticonvulsant potential of gap-junction blockers such as carbenoxolone, now in clinical use for treatment of ulcer disease, should be considered. [source] Anticonvulsant and antiepileptic actions of 2-deoxy-D-glucose in epilepsy models,ANNALS OF NEUROLOGY, Issue 4 2009Carl E. Stafstrom MD Objective Conventional anticonvulsants reduce neuronal excitability through effects on ion channels and synaptic function. Anticonvulsant mechanisms of the ketogenic diet remain incompletely understood. Because carbohydrates are restricted in patients on the ketogenic diet, we evaluated the effects of limiting carbohydrate availability by reducing glycolysis using the glycolytic inhibitor 2-deoxy-D-glucose (2DG) in experimental models of seizures and epilepsy. Methods Acute anticonvulsant actions of 2DG were assessed in vitro in rat hippocampal slices perfused with 7.5mM [K+]o, 4-aminopyridine, or bicuculline, and in vivo against seizures evoked by 6Hz stimulation in mice, audiogenic stimulation in Fring's mice, and maximal electroshock and subcutaneous pentylenetetrazol (Metrazol) in rats. Chronic antiepileptic effects of 2DG were evaluated in rats kindled from olfactory bulb or perforant path. Results 2DG (10mM) reduced interictal epileptiform bursts induced by 7.5mM [K+]o, 4-aminopyridine, and bicuculline, and electrographic seizures induced by high [K+]o in CA3 of hippocampus. 2DG reduced seizures evoked by 6Hz stimulation in mice (effective dose [ED]50 = 79.7mg/kg) and audiogenic stimulation in Fring's mice (ED50 = 206.4mg/kg). 2DG exerted chronic antiepileptic action by increasing afterdischarge thresholds in perforant path (but not olfactory bulb) kindling and caused a twofold slowing in progression of kindled seizures at both stimulation sites. 2DG did not protect against maximal electroshock or Metrazol seizures. Interpretation The glycolytic inhibitor 2DG exerts acute anticonvulsant and chronic antiepileptic actions, and has a novel pattern of effectiveness in preclinical screening models. These results identify metabolic regulation as a potential therapeutic target for seizure suppression and modification of epileptogenesis. Ann Neurol 2009;65:435,448. 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