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

自发性癫痫大鼠（SER）是一种双突变体（zi/zi, te/tm），表现为强直性惊厥和缺席样癫痫发作。丙戊酸钠（VPA）是已知的有效治疗原发性全身性癫痫发作和缺席样癫痫发作在人类。我们之前的研究表明，急性给药VPA可以抑制SER的强直性和缺席样癫痫发作。本研究的目的是确定长期口服抗癫痫药物的临床特征是否对该动物有用。从7周龄开始使用含有1%或5% VPA的食物颗粒进行VPA慢性治疗，与对照组相比，显著延长了SER的生存时间。1和5% VPA组治疗10周后血浆VPA浓度分别为17.3和82.5 mg /ml。强直性惊厥在14周龄时完全发生（8.3次/2小时）。与对照组相比，1%（5.1次/2小时）和5%（2.1次/2小时）VPA组强直性惊厥明显受到抑制。此外，1 VPA组以突然出现5- 7hz峰和波复峰为特征的缺席样癫痫发作也受到抑制。对药物的抑制作用没有产生耐受性。这些结果与癫痫患者的结果一致。此外，1% VPA组肝功能未见异常，5% VPA组有GOT、GPT轻度升高。因此，这些结果表明SER在长期抗癫痫药物的临床评价中是有用的。

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.