Cannabinoid antagonist SLV326 induces convulsive seizures and changes in the interictal EEG in rats.

Martin F J Perescis,Natasja De Bruin,Gilles Van Luijtelaar,Clementina M Van Rijn,Lyudmila Vinogradova,Annika Lüttjohann,Chris Kruse,Liesbeth Heijink

doi:10.1371/journal.pone.0165363

Abstract

Cannabinoid CB1 antagonists have been investigated for possible treatment of e.g. obesity-related disorders. However, clinical application was halted due to their symptoms of anxiety and depression. In addition to these adverse effects, we have shown earlier that chronic treatment with the CB1 antagonist rimonabant may induce EEG-confirmed convulsive seizures. In a regulatory repeat-dose toxicity study violent episodes of “muscle spasms” were observed in Wistar rats, daily dosed with the CB1 receptor antagonist SLV326 during 5 months. The aim of the present follow-up study was to investigate whether these violent movements were of an epileptic origin. In selected SLV326-treated and control animals, EEG and behavior were monitored for 24 hours. 25% of SLV326 treated animals showed 1 to 21 EEG-confirmed generalized convulsive seizures, whereas controls were seizure-free. The behavioral seizures were typical for a limbic origin. Moreover, interictal spikes were found in 38% of treated animals. The frequency spectrum of the interictal EEG of the treated rats showed a lower theta peak frequency, as well as lower gamma power compared to the controls. These frequency changes were state-dependent: they were only found during high locomotor activity. It is concluded that long term blockade of the endogenous cannabinoid system can provoke limbic seizures in otherwise healthy rats. Additionally, SLV326 alters the frequency spectrum of the EEG when rats are highly active, suggesting effects on complex behavior and cognition.

Highlights

Cannabinoid antagonists have been of interest because of their high therapeutic potential for a wide range of ailments, including addiction, obesity and metabolic disorders [1]
Our combined EEG-behavioral study with Wistar rats chronically treated with the cannabinoid receptor type 1 (CB1) antagonist SLV326 showed two major findings
The behavioral spasms, which were observed during daily clinical observations, were identified as generalized convulsive seizures

Summary

Introduction

Cannabinoid antagonists have been of interest because of their high therapeutic potential for a wide range of ailments, including addiction, obesity and metabolic disorders [1]. Our study in healthy Wistar rats, which were neither prone to epilepsy nor had spontaneous seizures of any type, showed the occurrence of severe convulsive seizures after a few daily doses of this cannabinoid antagonist [6]. There is some evidence in humans: partial seizures were observed in a patient treated with rimonabant for obesity, and with a history of idiopathic generalized epilepsy [7]. Katona and Freund [8] already mentioned that cannabinoid antagonists may hold risks in individuals with a history of convulsive epilepsy

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Results

Conclusion