Effects of standard anticonvulsant drugs on different patterns of epileptiform discharges induced by 4-aminopyridine in combined entorhinal cortex–hippocampal slices

doi:10.1016/S0006-8993(99)02348-3

Brain Research

Volume 859, Issue 1, 17 March 2000, Pages 15-20

https://doi.org/10.1016/S0006-8993(99)02348-3 Get rights and content

Abstract

Application of 4-aminopyridine (4-AP) has previously been reported to produce different patterns of epileptiform discharges in entorhinal cortex (EC)–hippocampal slices: recurrent short discharges (RSDs) in hippocampal area CA1, seizure-like events (SLEs) and negative-going potentials (NGPs) in the medial entorhinal cortex (mEC). Using recordings of field potentials, we investigated the pharmacological effects of the clinically employed standard anticonvulsant drugs phenytoin (PHT), carbamazepine (CBZ), valproic acid (VPA) and phenobarbital (PHB) and those of pentobarbital (PB) on 4-AP-induced epileptiform activity. The anticonvulsant drugs showed different effects: SLEs were completely blocked by all tested drugs. Valproic acid, which suppressed all epileptiform activities, seemed to have the most fundamental effect of all drugs on 4-AP induced activity, because under phenytoin and carbamazepine, some epileptiform activity was still observable. The RSDs in hippocampal area CA1 of the hippocampus did not respond to the different anticonvulsants. In contrast, PB decreased the frequency of the RSDs in CA1 and enhanced the frequency of the NGPs in the EC. We propose that the activities induced by 4-AP in the combined entorhinal cortex–hippocampal slices may provide an in vitro model for the development of new drugs against difficult-to-treat focal epilepsy.

Introduction

4-Aminopyridine (4-AP) is a convulsant which induces different types of seizure activity dependent on mode of application and area studied. 4-AP is well know to interfere with different types of K⁺ channels. These include D type [25] and A type K⁺ currents [27] and a subportion of delayed rectifier currents 12, 14. As a consequence, neuronal activity increases and bursting behaviour can be induced. Moreover, transmitter release is strongly augmented involving both inhibitory and excitatory neurotransmitters 20, 26.

4-AP induces different types of epileptiform discharges in combined entorhinal cortex (EC)–hippocampal slices. These areas are intimately involved in generation of drug resistant temporal lobe epilepsies. We therefore wanted to know how different conventional anticonvulsant affect the different patterns of epileptiform discharges in this area.

Previous studies have shown that in hippocampal areas CA3 and CA1 short recurrent discharges dominate [24] and that only rarely SLEs occur in adult transverse slices. In contrast, in the EC, SLEs regularly occur. These are characterized by long-lasting slow negative field potential shifts superimposed by initially high frequency low amplitude and later by low frequency electrographic activity. It was shown that such seizure like events are associated with ionic shifts comparable to those observed during SLEs in the intact animals [13]. Between SLEs interictal discharges occur which are also associated with rises in [K⁺] comparable to those observed during interictal discharges in the penicillin focus [10] and other focus models in intact animals. This is in contrast to the short recurrent discharges in the hippocampus which are often thought to represent interictal discharges. These are not associated with larger rises in [K⁺]. This suggests that generation mechanisms for the short recurrent discharges in the hippocampus and the interictal discharges in the EC are different. In fact it has been previously shown that interictal discharges can persist after blockade of glutamate receptors, but they are sensitive to bicuculline [1]. This suggests that GABAergic mechanisms are involved in generation of these events.

Section snippets

Tissue preparation

Deeply ether-anesthetised Wistar rats of both sexes (6–8 weeks, 180–250 g) were decapitated and the brain was removed and immersed in artificial cerebrospinal fluid (ACSF) at 4°C. The brain was hemisected, and horizontal slices (400 μm) containing temporal cortex area 2 or 3, perirhinal cortex, EC, the dentate gyrus, hippocampal areas CA1–4 and the subiculum were prepared as previously described [11]. The slices were transferred to an interface recording chamber and continuously perfused (1.6

Discussion

The present data indicate that application of 4-AP is able to induce different patterns of epileptiform activity with different pharmacological properties.

It has been proposed [21] that the NGPs are initiated by synchronous firing of inhibitory interneurons. Furthermore, it has been reported that in the presence of NBQX and APV the remaining NGPs are completely blocked by application of bicuculline [2]. This was confirmed by our experiments; remaining potentials after application of fast

Acknowledgements

C. Brückner is a recipient of a grant from Schering foundation. We thank Dr. A. Draguhn and Dr. D. Schmitz for helpful discussion and Drs H.-J. Gabriel and H. Siegmund for technical support.

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Research reportEffects of standard anticonvulsant drugs on different patterns of epileptiform discharges induced by 4-aminopyridine in combined entorhinal cortex–hippocampal slices

Abstract

Introduction

Section snippets

Tissue preparation

Discussion

Acknowledgements

Neurosci. Lett.

Prog. Neurobiol.

Epilepsy Res.

Neurosci. Lett.

Eur. J. Pharmacol.

Brain. Res.

Epilepsy Res.

Synchronous GABA-mediated potentials and epileptiform discharges in the rat limbic system in vitro

J. Neurosci.

CA3-driven hippocampal–entorhinal loop controls rather than sustains in vitro limbic seizures

J. Neurosci.

Effect of anesthetic and convulsant barbiturates on N-methyl-d-aspartate receptor-mediated calcium flux in brain membrane vesicles

Pharmacology

Inhibition of gamma-aminobutyric acid uptake into astrocytes by pentobarbital

Can. J. Physiol. Pharmacol.

The effect of an iminostilbene derivative (G32883) on peripheral nerves

J. Med. Assoc. Ga.

Chronic epileptic foci in vitro in hippocampal slices from rats with the tetanus toxin epileptic syndrome

J. Neurophysiol.

Synaptic and intrinsic responses of medical entorhinal cortical cells in normal and magnesium-free medium in vitro

J. Neurophysiol.

Research report
Effects of standard anticonvulsant drugs on different patterns of epileptiform discharges induced by 4-aminopyridine in combined entorhinal cortex–hippocampal slices