Abstracts

Rationale: The spontaneously epileptic rat (SER) is a genetically defined animal model which shows both tonic convulsion and absence-like seizures after 8 weeks (wk) of age. We have previously demonstrated that the occurrence of tonic convulsion is inhibited when daily administration of levetiracetam (LEV) is given intraperitoneally to SER from 4 to 8 wk of age (i.e. before seizure onset). This study was performed to determine the antiepileptogenic effects of osmotic mini-pump delivered LEV on SER before seizure onset. In addition, the relationship between the blood concentration of LEV and the antiepileptic effects in SER was examined. Furthermore the study attempted to exact basic background information for further investigation of the antiepileptogenic mechanism of LEV.Methods: One hundred one SERs were devided into groups 1,2,3 and 4. In group 1,2, and 3, SERs were each implanted in the back from age 4−8 wk with an osmotic mini−pump containing physiological saline, 210 and 420 mg/ml of LEV, respectively. In group 4, each SER was implanted with the pump containing 420 mg/ml LEV from age 4 −8 wk and given additional 420 mg/ml from age 6 −8 wk. The solution containing LEV or physiological saline was delivered at the rate of 2.5 μl/hr. Body weights of each group and number of convulsive seizures induced by puff stimulation applied on the face in each SER every 5 min for 30 min on a weekly basis. Blood concentrations of LEV were measured at 6, 8 and 9 wk of ages.Results: The number of convulsion observed after pump removal were significantly decreased in a dose−dependent manner in groups 2,3 and 4. The inhibition of the seizures was observed for 6 wk after removal of LEV−containing pump: the mean numbers of the convulsive seizures in groups 1,2,3 and 4 were 3.8±0.3 (n=28), 2.3±0.8 (n=7), 3.0±0.6 (n=10) and 2.1±0.5 (n=14) at age of 16 wk (8 wk after pump removal), respectively. The dose−dependent increase in blood concentration of LEV were observed in LEV−treated groups at ages of 6 and 8 wk (group3: 28.45 and 18.32 μg/ml; group 4: 29.95 and 34.32 μg/ml, respectively), but not at age of 9 wk in any groups. There were no significant differences in body weight changes among the 4 groups.Conclusions: LEV delivered by mini-pump subcutaneously before onset of epileptic seizures inhibited the convulsive seizures even when drug administration was terminated for long time (6 wk observed), suggesting that LEV inhibits epileptogenic mechanism. This study, therefore, established an experimental method for examining mechanism underlying antiepileptogenic effects of LEV and possibly other drugs as well.