UCB Biopharma SPRL, Neuroscience TA, Braine l'Alleud, Belgium.
Epilepsia. 2015 Feb;56(2):310-8. doi: 10.1111/epi.12893. Epub 2014 Dec 19.
The 6 Hz model of focal seizures has been increasingly used to identify anticonvulsant compounds with potential activity against therapy-resistant epilepsy, but the protective response to anticonvulsants in this model could be dependent on experimental conditions and selection of mouse strains.
Seizure thresholds in the 6 Hz model were compared in CF-1, NMRI, and C57Bl/6J male mice with two different electrical stimulators (Ugo Basile 5780 and Grass S48). Dose-response curves for phenytoin and levetiracetam were generated in the three strains at 32 and 44 mA current intensities using both devices. Plasma and brain exposure to the two drugs were measured in all three strains.
CF-1 mice had the lowest seizure threshold and responded to phenytoin at 32 mA stimulation intensity, but not at 44 mA. NMRI and C57Bl/6J mice had nearly identical threshold values, but NMRI mice responded well to phenytoin at 32 mA and showed limited responsiveness to this drug at 44 mA, whereas C57Bl/6J mice were nearly completely resistant to phenytoin. Furthermore, levetiracetam showed limited efficacy and low potency in CF-1 and C57Bl/6J mice, particularly at 44 mA, whereas in NMRI mice the drug showed much higher potency in all experimental conditions. No obvious difference in the pharmacokinetics of both phenytoin and levetiracetam was detected between the mouse strains that would have explained these unexpected variations in potency. We have also found that the protective effects of both drugs may be influenced by the device type.
Collectively these observations clearly indicate that treatment resistance of 6 Hz seizures should be interpreted with strain and experimental conditions in mind. Furthermore, it is important to note that strain differences, much like human genetic differences, may explain why some mice and patients respond to a given treatment and others do not.
6 Hz 局灶性癫痫模型已被越来越多地用于鉴定具有潜在治疗耐药性癫痫作用的抗惊厥化合物，但该模型中抗惊厥药物的保护反应可能依赖于实验条件和小鼠品系的选择。
使用两种不同的电刺激器（Ugo Basile 5780 和 Grass S48），比较 CF-1、NMRI 和 C57Bl/6J 雄性小鼠在 6 Hz 模型中的癫痫发作阈值。在这三种品系中，使用两种设备，在 32 和 44 mA 电流强度下生成苯妥英和左乙拉西坦的剂量-反应曲线。在所有三种品系中测量两种药物的血浆和脑暴露。
CF-1 小鼠的癫痫发作阈值最低，对 32 mA 刺激强度的苯妥英有反应，但对 44 mA 无反应。NMRI 和 C57Bl/6J 小鼠的阈值值几乎相同，但 NMRI 小鼠对 32 mA 的苯妥英反应良好，而对 44 mA 的苯妥英反应有限，而 C57Bl/6J 小鼠对苯妥英几乎完全耐药。此外，左乙拉西坦在 CF-1 和 C57Bl/6J 小鼠中的疗效有限，效力较低，尤其是在 44 mA 时，而在 NMRI 小鼠中，该药物在所有实验条件下均具有更高的效力。在解释这些效力的意外变化时，没有发现两种药物在小鼠品系之间的药代动力学有明显差异。我们还发现，两种药物的保护作用可能受到设备类型的影响。
综上所述，这些观察结果清楚地表明，应考虑品系和实验条件来解释 6 Hz 癫痫发作的治疗耐药性。此外，重要的是要注意，与人类遗传差异一样，品系差异可能解释为什么某些小鼠和患者对特定治疗有反应，而其他患者则没有。
