Diphenytoin, riluzole and lidocaine: Three sodium channel blockers, with different mechanisms of action, decrease hippocampal epileptiform activity (original) (raw)
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Journal of Neurophysiology, 1998
Transient suppression of creases in GABAergic inhibition facilitate the induction of GABA A-receptor-mediated IPSPs after epileptiform burst dislong-term potentiation (LTP) (Stelzer et al. 1994; Wigstrom charges in CA1 pyramidal cells. J. Neurophysiol. 79: 659-669, and Gustafsson 1983) and the onset of certain types of epi-1998. Epileptiform burst discharges were elicited in CA1 hippoleptic activity (Stelzer et al. 1987). Considerable evidence campal pyramidal cells in the slice preparation by perfusion with suggests that DSI is dependent on an influx of Ca 2/ into the Mg 2/-free saline. Intracellular recordings revealed paroxysmal depyramidal cell after the depolarizing stimulus (Pitler and polarization shifts (PDSs) that either occurred spontaneously or Alger 1992a). This Ca 2/ influx then triggers the induction were evoked by stimulation of Schaffer collaterals. These bursts of a retrograde signal, which causes a transient decrease in involved activation of N-methyl-D-aspartate receptors because GABA release from the presynaptic terminal (Alger and burst discharges were reduced or abolished by DL-2-amino-5-phosphonovaleric acid. Bath application of carbachol caused an increase Pitler 1995; Pitler and Alger 1992a, 1994). A recent study in spontaneous activity that was predominantly due to g-aminobuproposed that glutamate, or a glutamate-like substance, is tyric acid-A-receptor-mediated spontaneous inhibitory postsynapthe retrograde messenger in cerebellum (Glitsch et al. 1996). tic potentials (sIPSPs). A marked reduction in sIPSPs (31%) was However, the identity of the retrograde messenger in the observed after each epileptiform burst discharge, which subsehippocampus remains to be determined. quently recovered to preburst levels after Ç4-20 s. This sIPSP In most studies of DSI, the depolarizing stimulus was suppression was not associated with any change in postsynaptic either brief trains of current pulses producing a series of membrane conductance. A suppression of sIPSPs also was seen action potentials or a 1-or 2-s depolarizing voltage step after burst discharges evoked by brief (100-200 ms) depolarizing delivered to the postsynaptic cell. The question remains current pulses. N-ethylmaleimide, which blocks pertussis-toxinwhether DSI occurs as a result of cell firing after synaptic sensitive G proteins, significantly reduced the suppression of sIPSPs seen after a burst response. When increases in intracellular stimulation. A single Ca 2/ spike is sufficient to produce Ca 2/ were buffered by intracellular injection of ethylene glycol DSI (Pitler and Alger 1994) , suggesting that DSI could bis(b-aminoethyl)ether-N,N,N,N-tetraacetic acid, the sIPSP supoccur under conditions in which there is sufficient influx pression seen after a single spontaneous or evoked burst discharge of Ca 2/ such as might occur, for example, during an epiwas abolished. Although we cannot exclude other Ca 2/-dependent leptiform burst discharge. Hippocampal pyramidal cells mechanisms, this suppression of sIPSPs shared many of the characcan fire burst responses under both normal (Kandel et teristics of depolarization-induced suppression of inhibition (DSI) al. 1961) and epileptic conditions. Burst responses are in that it involved activation of G proteins and was dependent on composed, at least in part, of a voltage-dependent Ca 2/ increases in intracellular calcium. These findings suggest that a component (Schwartzkroin and Prince 1978; Wong and DSI-like process may be activated by the endogenous burst firing Prince 1979). The aim of this study was, therefore, to of CA1 pyramidal neurons.
Brain Research, 1992
The relation between interictal bursts (llBs) and seizures in epilepsy is obscure. Results from some human and animal studies suggest that llBs may actually suppress seizure activity. This appears particularly true in the zero magnesium in vitro seizure model. Here we provide new evidence in support of this and new insight into the mechanisms of seizure suppression in this model. Brain slices containing hippocampus and entorhinal cortex were bathed in zero magnesium medium. Electrographic seizures appeared, then were replaced by llBs. Upon lowering [K ~" ]o and raising [Ca: ~" ],, the lifts disappeared and the seizures reappeared. Repeated stimuli mimicking IIBs then suppressed seizures again. Selective knife cuts revealed that the IIBs originated in the hippocampus (area CA3) whereas the seizures originated in entorhinal cortex. These results confirm that IIBs suppress seizures in the zero magnesium model. They also show that an important aspect of the interaction between iiBs and seizures in this model is the anatomical segregation of their respective sites of origin. This may apply in other models and in human epilepsy as well. Finally, these results iPlustrate that one consequence of the anatomical segregation and mutual interaction of llBs and seizures is that influences which are locally pro-or antiepileptic can have opposite effects in a broader region.
Journal of Neurophysiology, 1987
Intracellular and extracellular recordings were made from pyramidal neurons in hippocampal slices in order to study spontaneous paroxysmal bursting induced by raising the extracellular potassium concentration from 3.5 to 8.5 mM. Extracellular recordings from all hippocampal subfields indicated that spontaneous bursts appeared to originate in region CA3c or CA3b as judged by burst onset. Burst intensity was also greatest in regions CA3b and CA3c and became progressively less toward region CA2. Intracellular recordings indicated that in 8.5 mM potassium, large spontaneous excitatory postsynaptic potentials (EPSPs), large burst afterhyperpolarizations, and rhythmic hyperpolarizing-depolarizing waves of membrane potential were invariably present in CA3c neurons. High potassium (8.5 mM) induced a positive shift (+9 mV) in the reversal potential of GABAergic inhibitory postsynaptic potentials (IPSPs) in CA3c neurons without changing input resistance or resting potential. This resulted in ...
Experimental Brain Research, 1990
We studied the effects of the organic calcium channel blocker, verapamil, on spontaneous and bicuculline-induced epileptiform burst discharges in CA3 pyramidal cells of hippocampal slices. A transient increase of burst discharge rate was observed in most cells within 30 min after the addition of verapamil (100 #M) to the perfusing medium. Prolonged verapamil perfusions gradually reduced the rate and duration of burst discharges, then abolished them in all tested slices (over periods of 50-150 min) without blocking synaptic transmission. Responses to intracellular injections of current pulses were also gradually affected by verapamil: Action potential amplitude was decreased, action potential duration increased, frequency adaptation increased, amplitude of the fast hyperpolarization following a single action potential decreased, and amplitude and duration "of the slow afterhyperpolarization markedly reduced. The amplitude of calcium spikes elicited in slices perfused with tetrodotoxin-containing medium was not affected by verapamil, but the mean velocity of depolarization near the peak of the calcium spike was decreased. Membrane resting potential and input resistance were not affected by verapamil. These results confirm that verapamil is able to suppress epileptiform activity, but suggest that this effect is rather non-specific, due to inhibition of both postsynaptic sodium and calcium conductances.
Selective central nervous system calcium channel blockers—A new class of anticonvulsant agents
The Journal of Emergency Medicine, 1986
Current research suggests that Ca 2+ flux into the neuron may be a critical factor in the genesis of seizures. We report herein the influence of nimodipine, a selective central nervous system calcium channel blocker, in 60 rabbits with seizures that had been induced through ischemia, postischemia reperfusion, pentylenetetrazol, and bicuculline. In 30 animals subjected to 4 hours of ischemia, 9 of the 15 control animals had seizures in comparison with 1 of the 15 treated animals (P<0.005). Five animals with reperfusion seizures demonstrated similar results. In 10 animals in which a convulsant was applied topically to both cerebral hemispheres, unilateral intracarotid injection of nimodipine arrested seizures in that hemisphere alone, whereas the control contralateral hemisphere continued to have electrical seizure activity (P<0.001). Both placebo and verapamil were ineffective. These results suggest that Ca 2+ influx is a common biochemical precipitant for various types of experimental seizures. Selective central nervous system calcium channel blockers may prove to be a new class of anticonvulsant agents. Approximately 1% of the population of the world suffer from epilepsy. 1 A substantial percentage of these patients are refractory to current medical treatment. For example, 30% of patients with temporal lobe epilepsy have persistent seizures despite maximal pharmacologic therapy. 2 Therefore, there is a demand for new anticonvulsant agents. In clinical epilepsy, excessive discharge of cortical neurons is the basic dysfunction at the cellular
Journal of Neurophysiology, 2006
Calcium-activated afterhyperpolarizations regulate synchronization and timing of epileptiform bursts in hippocampal CA3 pyramidal neurons. . Calcium-activated potassium conductances regulate neuronal excitability, but their role in epileptogenesis remains elusive. We investigated in rat CA3 pyramidal neurons the contribution of the Ca 2ϩ -activated K ϩ -mediated afterhyperpolarizations (AHPs) in the genesis and regulation of epileptiform activity induced in vitro by 4-aminopyridine (4-AP) in Mg 2ϩ -free Ringer. Recurring spike bursts terminated by prolonged AHPs were generated. Burst synchronization between CA3 pyramidal neurons in paired recordings typified this interictal-like activity. A downregulation of the medium afterhyperpolarization (mAHP) paralleled the emergence of the interictallike activity. When the mAHP was reduced or enhanced by apamin and EBIO bursts induced by 4-AP were increased or blocked, respectively. Inhibition of the slow afterhyperpolarization (sAHP) with carbachol, t-ACPD, or isoproterenol increased bursting frequency and disrupted burst regularity and synchronization between pyramidal neuron pairs. In contrast, enhancing the sAHP by intracellular dialysis with KMeSO 4 reduced burst frequency. Block of GABA A-B inhibitions did not modify the abnormal activity. We describe novel cellular mechanisms where 1) the inhibition of the mAHP plays an essential role in the genesis and regulation of the bursting activity by reducing negative feedback, 2) the sAHP sets the interburst interval by decreasing excitability, and 3) bursting was synchronized by excitatory synaptic interactions that increased in advance and during bursts and decreased throughout the subsequent sAHP. These cellular mechanisms are active in the CA3 region, where epileptiform activity is initiated, and cooperatively regulate the timing of the synchronized rhythmic interictal-like network activity.
Drug Development Research, 1986
Comparative action of flunarizine, phenytoin, carbamazepine and two calcium-entry blockers on spontaneous epileptiform bursts in the low calcium-hippocampal slice preparation. Drug Dev. Res. a:397-405,1986 Exposure of hippocampal slices to a medium containing a low Ca2+-concentration and an increased concentration of Mg2+ and K+ resulted in the blockade of synaptic transmission and the development of spontaneous synchronized epileptiform bursts (SSEB) in area CA1. The SSEBs were measured extracellularly as a negative potential shift with superimposed population spikes. Flunarizine is a "Ca2+-entry blocker" with antiepileptic actions in humans. We compared flunarizine with two reference antiepileptics (phenytoin and carbamazepine) and two other "Ca2+-entry blockers" (verapamil and nimodipine) for their ability to reduce SSEBs. Flunarizine, which is insoluble in ACSF bathing medium, was applied in a nanodrop directly onto the CA1 region of the slice. All other drugs were applied in the bathing medium. Flunarizine (1 picomol), phenytoin (2 x M), and carbamazepine (5 x loL6, 5 x M) and verapamil (2 x M) were ineffective. Increases in extracellular K+ occurred synchronously with, and decreases in extracellular Ca2+ followed, negative potential deflections during SSEBs. As the amplitude of potential shifts decreased after flunarizine so did the ion-shifts. Since M) reduced the SSEBs. Nimodipine (1 x
Journal of Neurophysiology, 2009
Ionic mechanisms of spontaneous depolarizing rather than hyperpolarizing (Alger and Nicoll GABAergic events in rat hippocampal slices exposed to 4-amino-1982; Ben-Ari et al. 1989; Grover pyridine. J. Neurophysiol. 78: 2582-2591. Ion-selective (H / et al. 1993; Staley and K / ) microelectrode techniques as well as conventional extraet al. 1995; Xie and Smart 1991). One of and intracellular recordings were used to study the ionic mechathe most intriguing recent findings is the mutual excitatory nisms of propagating spontaneous GABAergic events (SGEs) in coupling that is mediated by GABA A receptors among interrat hippocampal slices exposed to 4-aminopyridine (4-AP, 50-100 neurons . This excitatory mM). All experiments were made in the presence of antagonists coupling results in a high degree of synchronization of the of ionotropic glutamate receptors [10 mM 6-nitro-7-sulphamoylbenzoquinoxaline-2,3-dione (NBQX) and 40 mM DL-2-amino-5-activity of individual interneurons, which makes populations phosphonopentanoic acid (AP5)]. The SGEs were composed of a of interneurons behave in a networklike manner (Aram et negative-going change in field potential with a temporally coincial. 1991; Michelson and Wong 1991, 1994; Perreault and dent increase (0.7 { 0.3 mM; mean { SE) in extracellular K / Avoli 1992). Factors that shape the collective behavior of ([K / ] o ) and an alkaline transient (0.01-0.08 units) in extracellular interneuronal networks are of much interest because syn-pH (pH o ) in stratum radiatum of the area CA1. Simultaneous intrachronized interneuronal activity appears to be capable of cellular recordings showed a triphasic hyperpolarization-depolarpromoting long-lasting excitatory responses in pyramidal ization-late hyperpolarization response in pyramidal cells. Applineurons (Kaila et al. 1997; Staley et al. 1995; Taira et al. cation of pentobarbital sodium (PB, 100 mM) decreased the inter-
Opposite effects of T- and L-type Ca2+ channels blockers in generalized absence epilepsy
European Journal of Pharmacology, 2000
The role of the T-type Ca 2q channel blocker, ethosuximide, the L-type Ca 2q channel blocker, nimodipine and L-type Ca 2q channel Ž w. x. opener, BAY K8644 1,4 Dihydro-2,6-dimethyl-5-nitro-4-trifluoromethyl-phenyl-3-pyridine carboxylic acid methyl ester , was investigated on spike-wave discharges in WAGrRij rats. This strain is considered as a genetic model for generalized absence epilepsy. A dose-dependent decrease in the number of spike-wave discharges was found after i.c.v. ethosuximide, an increase after i.p. nimodipine and a decrease after i.c.v. BAY K8644. BAY K8644 was also able to antagonise the effects of nimodipine. Preliminary data were obtained with two conotoxins, MVIIC and GVIA, which block PrQ-type and N-type Ca 2q channels, respectively. Only after i.c.v. administration of v-conotoxin GVIA were the number and duration of spike-wave discharges reduced, but animals showed knockout lying. The latter suggests behavioural or toxic effects and that the decrease in spike-wave activity cannot unequivocally be attributed to blockade of N-type Ca 2q channels. It can be concluded that T-and L-type Ca 2q channel blockers show opposite effects on spike-wave discharges. Furthermore, these w effects are difficult to explain in terms of a model for spindle burst activity in thalamic relay cells proposed by McCormick and Bal Sleep Ž. x and arousal: thalamocortical mechanisms.