Dupuis Nina, Matagne Alain, Staelens Ludovicus, Dournaud Pascal, Desnous Béatrice, Gressens Pierre, Auvin Stéphane
Inserm, U1141, Paris, France.
University Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, Paris, France.
Epilepsia. 2015 May;56(5):800-5. doi: 10.1111/epi.12973. Epub 2015 Mar 25.
Brivaracetam (BRV) is a new antiepileptic drug candidate rationally designed for high affinity and selectivity for the synaptic vesicle protein 2A. This study explored anti-ictogenic and antiepileptogenic effects of BRV in rats at different stages of development.
Using a rapid kindling model in P14, P21, P28, and P60 rats, we studied two doses of BRV: 10 and 100 mg/kg injected intraperitoneally 30 min before afterdischarge assessment. We also assessed blood and brain concentrations of BRV 30 min after the injection.
BRV 100 mg/kg significantly increased the afterdischarge threshold (ADT) at all ages, whereas BRV at 10 mg/kg increased ADT in P60, P28, and P21 rats. BRV also shortens the afterdischarge duration (ADD), achieving statistical significance with 10 and 100 mg/kg at P60 and with 100 mg/kg at P21. At P60, BRV increases the number of stimulations required to achieve a stage 4-5 seizure in a dose-dependent manner. At P28 and P21, BRV increased the number of stimulations required to develop a stage 4-5 seizure in a dose-dependent manner with almost complete elimination of stage 4-5 seizures. In contrast, at P14, BRV had no effect on the number of stage 4-5 seizures. An age-related decrease in blood and brain concentrations of BRV was observed 30 min after injection of BRV 10 mg/kg, whereas with 100 mg/kg there were no significant age-correlated differences in brain and serum BRV concentrations.
BRV exerted dose-dependent anti-ictogenic effects from P60 to P14 independent of brain maturation. BRV also exhibited antiepileptogenic effects at P60, whereas this effect need to be further evaluated at P28 and P21. We did not observe any effect on epileptogenesis at P14 at either dose.
布立伏胺（BRV）是一种新的抗癫痫药物候选物，其设计初衷是对突触囊泡蛋白2A具有高亲和力和选择性。本研究探讨了BRV在大鼠不同发育阶段的抗致痫和抗癫痫发生作用。
利用P14、P21、P28和P60大鼠的快速点燃模型，我们研究了两种剂量的BRV：在放电后评估前30分钟腹腔注射10和100mg/kg。我们还在注射后30分钟评估了BRV的血药浓度和脑内浓度。
100mg/kg的BRV在所有年龄段均显著提高了放电后阈值（ADT），而10mg/kg的BRV在P60、P28和P21大鼠中提高了ADT。BRV还缩短了放电后持续时间（ADD），在P60时10和100mg/kg以及在P21时100mg/kg达到统计学显著性。在P60时，BRV以剂量依赖性方式增加达到4-5期癫痫发作所需的刺激次数。在P28和P21时，BRV以剂量依赖性方式增加发生4-5期癫痫发作所需的刺激次数，几乎完全消除了4-5期癫痫发作。相比之下，在P14时，BRV对4-5期癫痫发作次数没有影响。注射10mg/kg的BRV后30分钟观察到BRV的血药浓度和脑内浓度随年龄下降，而注射100mg/kg时，脑内和血清BRV浓度没有显著的年龄相关性差异。
从P60到P14，BRV发挥剂量依赖性的抗致痫作用，与脑成熟无关。BRV在P60时也表现出抗癫痫发生作用，而在P28和P21时这种作用需要进一步评估。两种剂量在P14时我们均未观察到对癫痫发生有任何影响。
