Abstracts

Rationale: Pharmacological and molecular evidence indicate that the cannabinoid system may regulate seizure activity, thus providing a potential therapeutic approach for the treatment of epilepsy. While cannabinoid-receptor agonists may be anti-convulsant, the antagonist has been reported to be pro-convulsant, but possibly anti-epileptogenic (Chen et al., 2007, J. Neurosci. 27:46). The present study was designed to test the hypothesis that SR141716A, a cannabinoid-receptor antagonist, has anti-epileptogenic properties in the kainate animal model of acquired epilepsy. Methods: To test this hypothesis, male Sprague Dawley rats (n=35), implanted for electroencephalogram (EEG) recordings, were treated with repeated low doses of kainate (7.5 mg/kg). Immediately after the development of the first electrographic seizure during kainate-induced status epilepticus, either vehicle (alcohol/saline 1:20 ratio) or SR141716A (10 mg/kg) was injected intraperitoneal. Chronic video-EEG data were collected for 2-week periods separated by 6-week intervals. Results: In the first 2 weeks after status epilepticus, the proportion of animals with seizures was 52% (9/17) for the drug-treated animals and 57% (8/14) for the vehicle-treated animals. During the first 2-week recording epoch, the average seizure frequency was 0.71+0.24 seizures/day (n=9) for the drug-treated animals and 0.39 +0.12 seizures/day (n=8) for the vehicle-treated animals. In the second 2-week epoch (i.e., weeks 9 and 10 after kainate treatment), the average seizure frequency was 2.5 + 1.3 seizures/day (n=7) for the drug-treated animals and 0.52 + 0.11 seizures/day (n=7) for the vehicle-treated animals. Thus, no significant differences were found between SR141716A-treated and control animals during the early stages of epileptogenesis (i.e., slow growth phase), although we are continuing to monitor these animals to test whether the severity of fully-developed epilepsy is altered by SR141716A. Conclusions: Contradictory to the previous studies that suggested this compound may be anti-epileptogenic, the cannabinoid-receptor antagonist, SR141716A, had no detectable effect on the development of spontaneous recurrent seizures during the 2-month period after kainate-induced status epilepticus. Possible explanations for the discrepancy are the different assays of epileptogenesis, differences in the animal models of acquired epilepsy, and/or the complex nature by which cannabinoids influence neural circuits.