Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany.
Exp Neurol. 2012 Mar;234(1):70-84. doi: 10.1016/j.expneurol.2011.12.014. Epub 2011 Dec 19.
Despite a large therapeutic arsenal of old and new antiepileptic drugs (AEDs), there remains a substantial unmet need for the patients with refractory (AED-resistant) epilepsy. Animal models of refractory epilepsy are needed for at least two goals; (1) better understanding of the mechanisms underlying resistance to AEDs, and (2) development of more efficacious AEDs for patients with refractory seizures. It is only incompletely understood why two patients with seemingly identical types of epilepsy and seizures may respond differently to the same AED. Prompted by this well-known clinical phenomenon, we tested whether epileptic rats from the same epilepsy model respond differently to AEDs and previously discovered phenobarbital (PB) responsive and resistant animals in groups of rats in which epilepsy had been induced by sustained electrical stimulation of the basolateral amygdala (BLA). In the present study, we used the same approach for the widely used pilocarpine model of temporal lobe epilepsy. Epileptic rats from this model were continuously video/EEG monitored over seven consecutive weeks, starting with a predrug control period of two weeks, then two weeks of daily treatment with PB at maximum tolerated doses, and finally a postdrug control period of three weeks. In those rats that were included in response selection, 50% did not adequately respond to PB, whereas PB significantly decreased seizure frequency and severity in another 50% of the animals. Responders and nonresponders did not differ in predrug seizure frequency, PB plasma levels or hippocampal neurodegeneration, but behavioral differences were observed in anxiety models. These findings demonstrate that in the pilocarpine model, similar to epilepsy patients, epileptic rats differ in their response to an AED, which is most likely due to as yet unknown genetic factors.
尽管有大量的旧的和新的抗癫痫药物（AEDs）治疗武器，但对于耐药性（AED 耐药）癫痫患者仍存在很大的未满足的需求。需要有耐药性癫痫的动物模型，至少有两个目的；（1）更好地了解对 AED 耐药的机制，以及（2）为耐药性癫痫患者开发更有效的 AEDs。为什么两个看似患有相同类型的癫痫和癫痫发作的患者对相同的 AED 的反应可能不同，这一点仅部分理解。受这种众所周知的临床现象的启发，我们测试了来自同一癫痫模型的癫痫大鼠是否对 AEDs 有不同的反应，以及先前在因持续电刺激基底外侧杏仁核（BLA）而诱发癫痫的大鼠组中发现的苯巴比妥（PB）敏感和耐药动物。在本研究中，我们使用了相同的方法来研究广泛使用的颞叶癫痫匹罗卡品模型。来自该模型的癫痫大鼠在连续七周内进行视频/EEG 监测，从两周的预药物对照期开始，然后每天用最大耐受剂量的 PB 治疗两周，最后是三周的药物后对照期。在那些被纳入反应选择的大鼠中，有 50%的大鼠对 PB 反应不足，而 PB 显著降低了另外 50%动物的癫痫发作频率和严重程度。反应者和无反应者在预药物发作频率、PB 血浆水平或海马神经退行性变方面没有差异，但在焦虑模型中观察到行为差异。这些发现表明，在匹罗卡品模型中，与癫痫患者相似，癫痫大鼠对 AED 的反应不同，这很可能是由于尚未知的遗传因素。
