Original research article
Long-term disease-modifying effect of the endocannabinoid agonist WIN55,212-2 in a rat model of audiogenic epilepsy

https://doi.org/10.1016/j.pharep.2014.12.002Get rights and content

Abstract

Background

Modulation of the endocannabinoid (eCB) transmission is a promising approach to treating epilepsy. Animal models can be used to investigate this approach. Krushinsky-Molodkina (KM) rats have, genetically, audiogenic epilepsy. Moreover, in these animals, repeated induction of audiogenic seizures results in a progressive prolongation of the seizures, known as audiogenic kindling.

Methods

The present study evaluated, in these KM rats, acute and long-term effects of a single dose of 4 mg/kg of the cannabinoid-receptor agonist WIN55,212-2.

Results

Administration of the single dose of WIN55,212-2 one hour before the 4th seizure delayed the kindling process by two weeks, without any acute effect on the audiogenic seizures.

Conclusions

This result suggests that short-term potentiation of the eCB system might modify the epileptogenic disease process in patients with a progressive course of epilepsy.

Introduction

The endocannabinoid system is an attractive target for the treatment of epilepsy [1]. Endocannabinoids (eCBs) activate a presynaptic signaling system, that when active suppresses transmitter release: both excitatory and inhibitory ones [2], [3]. In this way, endocannabinoid signaling plays an important role in maintaining the synaptic activity within its normal physiological range since it allows rapid regulation of the excitatory/inhibitory balance [4].

In addition, the eCB system is closely involved in long-term synaptic plasticity [2], [3]. Pharmacological modulation of eCB signaling affects long-term function of epileptic networks [5], [6].

Cannabinoids can have paradoxical effects on the mammalian nervous system since they can block neuronal excitation but also augment it by blocking its inhibition [7]. Indeed, it is far from clear whether enhancement or suppression of the endocannabinoid system is beneficial for patients with epilepsy. In some animal models, a single administration of the antagonist SR141716 (rimonabant) before or during an epileptic seizure decreases remote enhancement of seizure susceptibility [5], [6], despite its acute pro-epileptic [4] and chronic pro-epileptogenic effects [8], in other models. Chen et al. [5] and Echegoyen et al. [6] suggest an anti-epileptogenic potency of transient suppression of eCB transmission in the beginning of the epileptogenic process. However, it is unknown how acute stimulation of eCB signaling in this period affects subsequent epileptogenesis. Repeated administration of the eCB agonist WIN55,212-2 (WIN) has been shown to retard electrical kindling [9] but the chronic treatment protocol complicates dissecting acute anticonvulsive and long-term anti-epileptogenic drug effects. The present study was designed to examine effects of WIN in a single-injection experiment in Krushinsky-Molodkina (KM) rats with genetic audiogenic epilepsy [10].

In KM rats audiogenic seizures can be evoked by acoustic stimulation [10]. Repetition of the seizures results in their prolongation, which is a reliable marker of the epileptogenic process called audiogenic kindling [11]. The behavioral manifestations of the audiogenic seizures and audiogenic kindling are well described and thus this animal model is well suited to test both acute and long term effects of drugs [11], [12]. First acoustic stimulations activate brainstem seizure networks and the motor seizures consist of running and tonic convulsions [10], [11], [13]. Repetition of these brainstem seizures recruits the forebrain into the epileptic network, which is manifested in the development of an additional seizure component: a post-tonic clonus (PTC). This component is the behavioral measure of secondary seizure generalization and thus of epileptogenesis.

The present study examined acute and long-term effects of a single administration of WIN in the early stage of audiogenic kindling.

Section snippets

Materials and methods

Adult male KM rats weighing 200–250 g were housed in groups of five per cage with free access to food and water. The experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and our protocol was approved by the Institutional Animal Care Committee.

Audiogenic seizures were elicited by a standard acoustic stimulus (13–85 kHz, 50–60 dB). The sound lasted until the onset of the seizure. Seizure latency was defined as the time

Results

In all rats the sound stimulation induced a severe two-phase audiogenic convulsion consisting of wild running and tonic components. With seizure repetition the severity and duration of the two seizure phases did not change but a new third seizure component appeared after the end of tonic convulsions namely the post-tonic clonus. The development of this new seizure phase led to progressive increase in the total duration of audiogenic seizures from 24.2 (0.5) s to 44.3 (7.0) s mean (SEM) (Fig. 1).

Discussion

The present study shows that treatment of Krushinsky-Molodkina (KM) rats with a single dose of the endocannabinoid (eCB) agonist WIN55,212-2 (WIN) delays development of audiogenic kindling with a period of two weeks, without any acute effect on the seizures. Since in these rats the kindling process is a manifestation of epileptogenesis, namely of seizure generalization from brainstem to forebrain [11], this result suggests a striking disease-modifying effect of this eCB agonist. The present

Conflict of interest

None declared.

Funding

This research was supported by Russian Fund of Basic Research nr 14-04-01184.

Acknowledgments

We cordially thank Prof. I.I. Poletaeva for donating Krushinsky-Molodkina rats and Alla Shatskova for technical assistance. We warmly acknowledge Drs. Jan Pieter Zwart for critical reading of the manuscript and for helpful suggestions.

References (19)

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