Brandt Claudia, Löscher Wolfgang
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
Epilepsy Res. 2014 Sep;108(7):1145-57. doi: 10.1016/j.eplepsyres.2014.05.008. Epub 2014 May 21.
About 25% of patients with epilepsy are refractory to treatment, so that new, more effective antiepileptic drugs (AEDs) are urgently needed. Animal models that simulate the clinical situation with individuals responding and not responding to treatment are important to determine mechanisms of AED resistance and develop novel more effective treatments. We have previously developed and characterized such a model in which spontaneous recurrent seizures (SRS) develop after a status epilepticus induced by sustained electrical stimulation of the basolateral amygdala. In this model, prolonged treatment of epileptic rats with phenobarbital (PB) results in two subgroups, PB responders and PB nonresponders. When PB nonresponders were treated in previous experiments with phenytoin (PHT), 83% of the PB-resistant rats were also resistant to PHT. In the present study we examined if rats with PB resistant seizures are also resistant to lamotrigine (LTG), using continuous EEG/video recording of spontaneous seizures over 10 consecutive weeks. For this purpose, a new group of epileptic rats was produced and selected by treatment with PB into responders and nonresponders. As in previous studies, PB nonresponders had a significantly higher seizure frequency before onset of treatment. During subsequent treatment with LTG, all PB nonresponders and 60% of the PB responders exhibited >75% reduction of seizure frequency and were therefore considered as LTG responders. Plasma levels of LTG did not differ significantly between responders and nonresponders. The data of this pilot study indicate that LTG is more effective than PHT to suppress seizures in PB nonresponders in this model, but that not all PB responders also respond to LTG. Overall, our data provide further evidence that AED studies in post-SE TLE models are useful in determining and comparing AED efficacy and investigating predictors and mechanisms of pharmacoresistance.
约25%的癫痫患者对治疗无效，因此迫切需要新的、更有效的抗癫痫药物（AEDs）。模拟个体对治疗有反应和无反应的临床情况的动物模型对于确定AED耐药机制和开发新的更有效治疗方法很重要。我们之前已经开发并描述了这样一种模型，在该模型中，通过持续电刺激基底外侧杏仁核诱导癫痫持续状态后会出现自发性反复癫痫发作（SRS）。在这个模型中，用苯巴比妥（PB）对癫痫大鼠进行长期治疗会产生两个亚组，PB反应者和PB无反应者。在之前的实验中，当用苯妥英（PHT）治疗PB无反应者时，83%的PB耐药大鼠也对PHT耐药。在本研究中，我们通过连续10周对自发性癫痫发作进行脑电图/视频记录，研究了PB耐药性癫痫大鼠是否也对拉莫三嗪（LTG）耐药。为此，通过用PB治疗产生并选择了一组新的癫痫大鼠，分为反应者和无反应者。与之前的研究一样，PB无反应者在治疗开始前癫痫发作频率显著更高。在随后用LTG治疗期间，所有PB无反应者和60%的PB反应者癫痫发作频率降低>75%，因此被视为LTG反应者。反应者和无反应者之间LTG的血浆水平没有显著差异。这项初步研究的数据表明，在该模型中，LTG比PHT更有效地抑制PB无反应者的癫痫发作，但并非所有PB反应者也对LTG有反应。总体而言，我们的数据进一步证明，在癫痫持续状态后颞叶癫痫模型中进行AED研究有助于确定和比较AED疗效，并研究药物耐药性的预测因素和机制。
