Abstracts

Rationale: No clinical therapies currently exist which combat epileptogenesis, the biological process(es) which transforms a healthy brain into an epileptic brain. Ethosuximide (ETX), a drug commonly used to reduce the occurrence of absence seizures in humans, has recently been shown to inhibit epileptogenesis in the WAG/Rij rodent model of idiopathic generalised epilepsy. Here, we investigated whether chronic ETX treatment was anti-epileptogenic in another polygenic rat model of absence epilepsy: the GAERS model. We also assessed whether drug treatment alleviated the behavioral abnormalities present in this strain. Methods: At 3 weeks of age, GAERS (n=5) and non epileptic control (NEC, n=7) rats were weaned on to ETX in drinking water, and by 6 weeks of age (prior to the normal onset of seizures in GAERS), received an average of 300 mg/kg/day. This treatment was continued until week 22, when all rats were switched to tap water. Control-treated GAERS (n=6) and NEC rats (n=4) received tap water throughout the study. All rats underwent serial 24 hour EEG recordings for seizure expression and behavioral testing for anxiety levels. Results: Prior to week 22 (when ETX treatment was ceased), ETX-treated GAERS spent significantly less time in seizure than control-treated GAERS (1.6 0.5% vs 7.1 1.1%; p=0.002). At week 34, at a time when ETX treatment had been ceased for 12 weeks, GAERS previously receiving treatment still exhibited significantly less seizure activity than controls (4.2 0.4% vs 7.0 0.7%; p=0.01). Anxiety levels, as assessed by total distance moved in the open field, were increased in GAERS compared with NEC rats, but this was reversed in ETX-treated GAERS, with a significant increase in distance travelled in treated GAERS compared with control-treated GAERS (3200 701cm vs 2218 275cm; p=0.04). Conclusions: These data demonstrate that ETX induces an anti-epileptogenic effect in GAERS, reducing seizure expression long after treatment has ceased. Behavioural deficits were also reduced following cessation of treatment, intimating a common causation between seizures and anxiety in this model. The ability of this drug to limit disease progression in a second rat model validates the hypothesis that anti-epileptogenic therapy is achievable, and prevention of epilepsy in humans with early treatment may be possible.