Löscher W, Cramer S, Ebert U
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Epilepsia. 1998 Nov;39(11):1138-47. doi: 10.1111/j.1528-1157.1998.tb01304.x.
We recently described that, by repeated testing of the anticonvulsant phenytoin (PHT), it is possible to select responders and nonresponders from large populations of amygdala-kindled Wistar rats. Whereas responders show marked and reproducible increases of focal seizure threshold (afterdischarge threshold: ADT) on repeated testing of PHT, 75 mg/kg i.p., nonresponders do not show any significant ADT increase after this dose, thus allowing use of these subgroups in the search for mechanisms of pharmacoresistance in temporal lobe epilepsy. In this study, we examined whether PHT responders and nonresponders can also be selected from large groups of kindled rats of the Sprague-Dawley strain.
Male and female Sprague-Dawley rats were amygdala kindled, followed by once weekly i.p. testing of PHT.
In contrast to recent experiments in Wistar rats, 75 mg/kg PHT did not induce significant ADT increases in Sprague-Dawley rats, indicating strain differences in response to this drug after kindling. When the dose was lowered to 50 or 25 mg/kg, significant and reproducible ADT increases were obtained in Sprague-Dawley rats of both genders. Therefore these doses were used for selection of responders and nonresponders in a total of 42 rats. Almost 50% of the rats were PHT responders, whereas no rat was a nonresponder when tested in up to six subsequent drug trials. Many rats were variable responders (i.e., showed ADT increases in some but not all trials), which was not due to low or variable drug absorption after i.p. injection.
The data indicate that, in contrast to Wistar rats, Sprague-Dawley rats are not suited for selection of PHT nonresponders, but rather are quite responsive to this drug. A further difference to the Wistar strain is the truncated dose-response with loss of anticonvulsant efficacy at 75 mg/kg in kindled Sprague-Dawley rats, which may, at least in part, explain the inconsistent results reported on the anticonvulsant efficacy of PHT in this strain in the literature. The lack of anticonvulsant activity after administration of 75 mg/kg may be a result of kindling, because administration of this dose before kindling causes a significant ADT increase in this strain. This kindling-induced alteration of the anticonvulsant activity of PHT is a phenomenon that contrasts Sprague-Dawley with Wistar rats and deserves further investigation.
我们最近描述了，通过反复测试抗惊厥药物苯妥英（PHT），可以从大量杏仁核点燃的Wistar大鼠群体中筛选出反应者和无反应者。在反复腹腔注射75mg/kg PHT测试时，反应者的局灶性癫痫发作阈值（后放电阈值：ADT）显著且可重复升高，而无反应者在该剂量后ADT没有显著升高，因此可以利用这些亚组来研究颞叶癫痫的耐药机制。在本研究中，我们检测了是否也能从大量Sprague-Dawley品系的点燃大鼠中筛选出PHT反应者和无反应者。
对雄性和雌性Sprague-Dawley大鼠进行杏仁核点燃，随后每周一次腹腔注射PHT进行测试。
与最近对Wistar大鼠的实验不同，75mg/kg PHT未引起Sprague-Dawley大鼠的ADT显著升高，表明点燃后该品系对这种药物的反应存在差异。当剂量降至50或25mg/kg时，雌雄Sprague-Dawley大鼠的ADT均显著且可重复升高。因此，使用这些剂量在总共42只大鼠中筛选反应者和无反应者。几乎50%的大鼠是PHT反应者，而在多达六次后续药物试验中测试时，没有一只大鼠是无反应者。许多大鼠是可变反应者（即，在某些但不是所有试验中ADT升高），这不是由于腹腔注射后药物吸收低或不稳定所致。
数据表明，与Wistar大鼠不同，Sprague-Dawley大鼠不适合筛选PHT无反应者，而是对这种药物相当敏感。与Wistar品系的另一个差异是，在点燃的Sprague-Dawley大鼠中，75mg/kg时抗惊厥疗效丧失，剂量反应曲线截断，这可能至少部分解释了文献中关于该品系PHT抗惊厥疗效报道结果不一致的原因。给予75mg/kg后缺乏抗惊厥活性可能是点燃的结果，因为在点燃前给予该剂量会导致该品系的ADT显著升高。这种点燃诱导的PHT抗惊厥活性改变是Sprague-Dawley大鼠与Wistar大鼠不同的一种现象，值得进一步研究。
