Establishment of evaluation of long-term effects of antiepileptic drugs in the spontaneously epileptic rat

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The spontaneously epileptic rat (SER) is a double mutant (zi/zi, te/tm) that exhibits both tonic convulsion and absence-like seizure. Sodium valproate (VPA) is known to be effective in the treatment of primary generalized seizures and absence-like seizures in humans. Our previous study demonstrates that an acute administration of VPA suppresses both tonic and absence-like seizures in SER. The study was performed to determine whether or not this animal is useful in evaluation of clinical characteristics of antiepileptics when the drugs were orally given for long-term period. Chronic treatment with VPA using food pellets containing either 1 or 5 % VPA from 7 weeks of age significantly prolonged the survival time of SER compared to the control. The plasma concentrations of VPA after 10-week treatment were 17.3 and 82.5 mug/ml in the 1 and 5 % VPA groups, respectively. Tonic convulsion fully developed at 14 weeks of age in the control group (8.3 times/2 hours). At the same age, the tonic convulsion in l % (5.1 times/2 hours) and 5 % (2.1 times/2 hours) VPA groups were significantly suppressed compared to the control group. In addition, absence-like seizures characterized by sudden appearance of 5-7 Hz spike and wave complex were also inhibited in 1 VPA group. There were no tolerance development to the inhibitory effects of the drugs. These results are in accordance with those seen in epileptic patients. Furthermore, there were no abnormal findings on liver function of 1 % VPA group except for slight elevation of GOT and GPT in 5 % VPA group. Thus, these results suggest that SER is useful in the evaluation of clinical profiles of antidpileptic drugs for longterm period.