Suppression by topiramate of epileptiform burst discharges in hippocampal CA3 neurons of spontaneously epileptic rat in vitro

Hanaya, Ryosuke; Sasa, Masashi; Ujihara, Hisamitsu; Ishihara, Kumatoshi; Serikawa, Tadao; Iida, Koji; Akimitsu, Tomohide; Arita, Kazunori; Kurisu, Kaoru

doi:10.1016/s0006-8993(98)00116-4

Cited by 39 publications

(20 citation statements)

References 12 publications

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“…Interestingly, both L‐type and non–L‐type currents may be enhanced by TPM at higher concentrations, suggesting a complex mechanism of action (9,14). In contrast, TPM had no effect on Ca 2+ spikes or whole‐cell Ca 2+ currents in hippocampal CA3 neurons (15). Similarly, we did not observe a depression of Ca 2+ spikes by TPM in control conditions.…”

Section: Discussionmentioning

confidence: 99%

Topiramate Inhibits the Initiation of Plateau Potentials in CA1 Neurons by Depressing R‐type Calcium Channels

et al. 2005

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Summary:Purpose: Cholinergic-dependent plateau potentials (PPs) are intrinsically generated conductances that can elicit ictal-type seizure activity. The aim of this study was to investigate the actions of topiramate (TPM) on the generation of PPs.Methods: We used whole-cell patch-clamp recordings from CA1 pyramidal neurons in rat hippocampal slices to examine the effects of TPM on the PPs.Results: In current-clamp mode, action potentials evoked PPs after cholinergic receptor stimulation. Therapeutically relevant concentrations of TPM (50 µM) depressed the PPs evoked by action potentials. Surprisingly, in voltage-clamp mode, we discovered that the cyclic nucleotide-gated (CNG) current that underlies PP generation (denoted as I tail ) was not depressed. However, significantly longer depolarizing voltage steps were required to elicit I tail . This suggested that the calcium entry trigger for evoking PPs was depressed by TPM and not I tail itself. TPM had no effect on calcium spikes in control conditions; however, TPM did reduce calcium spikes after cholinergic-receptor stimulation. We recently found that R-type calcium spikes are enhanced by cholinergic-receptor stimulation. Therefore we isolated Rtype calcium spikes with a cocktail containing tetrodotoxin, ω-conotoxin MVIIC, ω-conotoxin-GVIA, ω-agatoxin IVA, and nifedipine. R-type calcium spikes were significantly depressed by TPM. We also examined the effects of TPM on recombinant Ca V 2.3 calcium channels expressed in tsA-201 cells. TPM depressed currents mediated by Ca V 2.3 subunits by a hyperpolarizing shift in steady-state inactivation.Conclusions: We have found that TPM reduces ictallike activity in CA1 hippocampal neurons through a novel inhibitory action of R-type calcium channels.

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Section: Discussionmentioning

confidence: 99%

Topiramate Inhibits the Initiation of Plateau Potentials in CA1 Neurons by Depressing R‐type Calcium Channels

et al. 2005

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“…117 It also blocked repetitive firing in hippocampal CA3 neurons from spontaneously epileptic rats, and reduced excitatory post-synaptic potentials and responses to bath-applied glutamate, suggesting blockade of post-synaptic glutamate receptors, 118 affecting kainate-evoked but not NMDA-evoked currents. 119 Topiramate also inhibited both L-type and non L-type high voltage activated calcium currents 120 and reduced bicarbonate production via inhibition of carbonic anhydrase, 121 which may contribute to its antiseizure effect.…”

Section: Gabaar Effects Of Other Asdsmentioning

confidence: 92%

Molecular mechanisms of antiseizure drug activity at GABAA receptors

Greenfield

2013

Seizure

160

129

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The GABAA receptor (GABAAR) is a major target of antiseizure drugs (ASDs). A variety of agents that act at GABAARs s are used to terminate or prevent seizures. Many act at distinct receptor sites determined by the subunit composition of the holoreceptor. For the benzodiazepines, barbiturates, and loreclezole, actions at the GABAAR are the primary or only known mechanism of antiseizure action. For topiramate, felbamate, retigabine, losigamone and stiripentol, GABAAR modulation is one of several possible antiseizure mechanisms. Allopregnanolone, a progesterone metabolite that enhances GABAAR function, led to the development of ganaxolone. Other agents modulate GABAergic “tone” by regulating the synthesis, transport or breakdown of GABA. GABAAR efficacy is also affected by the transmembrane chloride gradient, which changes during development and in chronic epilepsy. This may provide an additional target for “GABAergic” ASDs. GABAAR subunit changes occur both acutely during status epilepticus and in chronic epilepsy, which alter both intrinsic GABAAR function and the response to GABAAR-acting ASDs. Manipulation of subunit expression patterns or novel ASDs targeting the altered receptors may provide a novel approach for seizure prevention.

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“…TPM, acting through multiple mechanisms, inhibits voltage‐ and receptor‐gated calcium channels, voltage‐dependent chloride channels, and excitatory neurotransmission. Moreover, TPM prevents seizure‐induced hippocampal neuronal injury in animal models such as kindled seizures and ischemia (Hanaya et al, 1998), as well as excitotoxic damage in newborn mice, as indicated by reduced terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) and cleavage of caspase‐3 (Sfaello et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Protective effect of topiramate on kainic acid–induced cell death in mice hippocampus

et al. 2007

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SUMMARYThe protective effect of topiramate (TPM) on seizure-induced neuronal injury is well known; however, its molecular basis has yet to be elucidated. We investigated the effect and signaling mediators of TPM on seizure-induced hippocampal cell death in kainic acid (KA)-treated ICR mice. KA-induced hippocampal cell death was identified by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Immunoreactivity (IR) of p-Erk, p-Jnk, p-P38, and caspase-3, and caspase-3 activity were observed in the hippocampal region 3 h after KA (0.1 µg/5 µL, i.c.v.) administration, and/or TPM (100 mg/kg, i.p.) pretreatment. TPM attenuated seizure-induced neuronal cell death and reduced KA-induced p-Erk IR in the CA3 region of the hippocampus, but did not affect p-Jnk and p-P38. In addition, TPM reduced caspase-3 IR and activation by KA. KA-induced seizures were also suppressed by TPM pretreatment. TPM inhibits seizures, and decreases Erk phosphorylation and caspase-3 activation by KA, thereby contributing to protection from neuronal injury.

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Suppression by topiramate of epileptiform burst discharges in hippocampal CA3 neurons of spontaneously epileptic rat in vitro

Cited by 39 publications

References 12 publications

Topiramate Inhibits the Initiation of Plateau Potentials in CA1 Neurons by Depressing R‐type Calcium Channels

Topiramate Inhibits the Initiation of Plateau Potentials in CA1 Neurons by Depressing R‐type Calcium Channels

Molecular mechanisms of antiseizure drug activity at GABAA receptors

Protective effect of topiramate on kainic acid–induced cell death in mice hippocampus

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