Effects of lamotrigine and levetiracetam on seizure development in a rat amygdala kindling model

doi:10.1016/S0920-1211(02)00254-1

Epilepsy Research

Volume 53, Issues 1–2, February 2003, Pages 95-106

https://doi.org/10.1016/S0920-1211(02)00254-1 Get rights and content

Abstract

In kindling models of epilepsy, the period during which repeated stimulation evokes intensifying seizures is attributed to an underlying epileptogenic process, and the point at which class 5 kindled seizures occur is considered the established epileptic state. Previous studies have indicated that a separation can occur between drug effects on these two components. For example, carbamazepine and phenytoin inhibit kindled seizures but have no effect on seizure development, whereas levetiracetam inhibits both components. We have investigated the profile of lamotrigine in the amygdala kindling model, including levetiracetam for comparison. As expected, both treatments dose-dependently inhibited class 5 kindled seizures. In a separate study, daily administration of either lamotrigine (20 mg kg⁻¹ i.p.) or levetiracetam (50 mg kg⁻¹ i.p.) demonstrated antiepileptogenic-like effects by blocking seizure development during the treatment period. Following cessation of drug treatment, further daily stimulation resulted in kindled seizure development, though there was a significant increase with both treatment groups, relative to the control group, in the total number of stimulations required to produce classes 3 and 5 seizures. In addition, prior levetiracetam treatment appeared to delay or prevent the expected increase in after-discharge duration (ADD). These results suggest that lamotrigine, like levetiracetam, possesses the ability to counteract kindling acquisition, which differentiates it from other drugs with sodium channel blocking activity.

Introduction

The electrical kindling model is widely used to predict the efficacy of anticonvulsants against partial seizures. Kindling is the phenomenon by which repeated application of an initially sub-convulsive electrical stimulation, via chronically-implanted electrodes, to a discrete locus in the brain produces progressively intense and persistent partial seizures with secondary generalisation (Goddard et al., 1969). For kindling to develop, the stimulation must produce an after-discharge from neurones at the site of stimulation. This can be visualised by electrographic recording following the stimulation (Racine, 1972).

It has been hypothesised that during the development of certain types of epilepsy, particularly those with partial onset seizures, an increasing susceptibility to seizure results from limbic cell loss and maladaptive changes in brain structure and function (De Lanerolle et al., 1989). Therefore, therapeutic strategies that address these underlying pathophysiological processes may have the potential for preventing the development or progression of epilepsy. In kindling models of epilepsy, the period during which repeated stimulation evokes progressively intense seizures is also attributed to an underlying epileptogenic process, a pathophysiological process involving alterations in dendritic spine morphology, limbic cell loss and aberrant synaptogenesis in the hippocampus (Sutula et al., 1994). Therefore, the kindling period provides a means of testing putative antiepileptogenic compounds (Racine et al., 1975, McNamara et al., 1985). The number of stimulations required to produce a class 5 kindled seizure can be used to quantify the epileptogenic process.

A small number of drugs, including both clinically-effective antiepileptic drugs (AEDs) such as sodium valproate (Silver et al., 1991), and experimental tools such as MK-801 (McNamara et al., 1988) or 2-chloroadenosine (Abdul-Ghani et al., 1997), have been reported to delay the kindling process. More recently, it has been suggested that the novel AED levetiracetam may be antiepileptogenic since it delays the kindling process as well as inhibiting class 5 kindled seizures (Löscher et al., 1998). However, this effect does not appear to be true for all AEDs that inhibit class 5 kindled seizures, since the sodium channel blocker, carbamazepine, had no effect on the development of seizures over the dose range tested (Silver et al., 1991).

The aim of the present study was to determine whether lamotrigine (Lamictal^®), in addition to its broad-spectrum anticonvulsant profile (Miller et al., 1986), also demonstrates antiepileptogenic-like activity in the kindling model. We have therefore tested lamotrigine and levetiracetam in the amygdala kindling model, using the methodology of Silver et al. (1991).

Section snippets

Animals

Adult male Lister hooded rats (280–350 g at time of surgery; Glaxo Wellcome Rodent Breeding Unit) were housed in groups of five prior to surgery, and in pairs post-surgery, under normal holding conditions (20–22 °C, 45–70% humidity, 12 h light-dark cycle, lights on 7:00 h). The study was conducted in accordance with UK Home Office regulations.

Chronic implantation of electrodes into the amygdala

Rats were anaesthetised with a Hypnorm/Hypnovel mixture (1.1 ml kg⁻¹ s.c. of Hypnovel (midazolam 2 mg ml⁻¹), followed by 1.1 ml kg⁻¹ s.c. of Hypnorm (fentanyl 0.315

Anticonvulsant protocol

In fully kindled rats, pre-treatment with lamotrigine (5–20 mg kg⁻¹ p.o.), 2 h prior to electrical stimulation of the amygdala, reduced seizure severity and ADD in a dose-related manner (Fig. 1A and Table 2). The estimated ED₅₀ for reducing ADD was 14 mg kg⁻¹. Similarly, pre-treatment with levetiracetam (12.5–50 mg kg⁻¹ i.p.), 1 h prior to electrical stimulation of the amygdala also reduced seizure severity and ADD in a dose-related manner (Fig. 1B and Table 2). The estimated ED₅₀ for reducing ADD was

Discussion

Data from the present study confirms the anticonvulsant effects of lamotrigine and levetiracetam against complex partial seizures, with both agents producing a reduction in seizure severity in amygdala kindled rats. These results are in agreement with previous reports of the anticonvulsant effects of these agents in rodent kindling models (Loscher and Honack, 1993, Otsuki et al., 1998).

Furthermore, both lamotrigine and levetiracetam demonstrated an antiepileptogenic-like effect by blocking the

Acknowledgements

We wish to thank members of BioSciences Support, GlaxoSmithKline (Stevenage, UK), for their assistance with dosing and care of the animals throughout the study. We also wish to thank Dr. David Hosford and Professor James McNamara for their critical review of the manuscript, and Mr. Philip Overend for extensive statistical analysis. These data were presented in part at the European Congress of Epileptology, Florence, 2000.

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Effects of lamotrigine and levetiracetam on seizure development in a rat amygdala kindling model

Abstract

Introduction

Section snippets

Animals

Chronic implantation of electrodes into the amygdala

Anticonvulsant protocol

Discussion

Acknowledgements

Eur. J. Pharmacol.

Brain Res.

Epilepsy Res.

Exp. Neurol.

Neurosci. Lett.

Eur. J. Pharmacol.

Neuropharmacology

Epilepsy Res.

Neuropharmacology

Epilepsy Res.

Epilepsy Res.

Electroenceph. Clin. Neurophysiol.

Electroenceph. Clin. Neurophysiol.

Brain Res.