Neurology Tsukuba Research Department, Discovery, Medicine Creation, Neurology Business Group, Eisai Co., Ltd. Japan.
Clinical Science Department, Medical Division, Eisai Co., Ltd. Nishigokencho 13-1, Shinjuku-ku, Tokyo 162-0812, Japan.
Epilepsy Res. 2019 Aug;154:42-49. doi: 10.1016/j.eplepsyres.2019.03.011. Epub 2019 Apr 15.
A number of antiepileptic drugs (AEDs) with a variety of modes of action, are effective in treating focal seizures. Several AEDs, such as perampanel (PER), levetiracetam (LEV), lacosamide (LCM), lamotrigine (LTG), and carbamazepine (CBZ), have been shown to elevate the seizure threshold in kindling models. These AEDs are clinically effective, but differences exist in the anti-seizure profiles of drugs with similar modes of action. Therefore, we hypothesized that there are differences in how these AEDs affect seizures. Here, we evaluated the effects of AEDs on various seizure parameters in a rat amygdala kindling model upon stimulation at the after-discharge threshold (ADT) and at three-times the ADT (3xADT) to characterize the differences in the effects of these AEDs.
PER, LEV, LCM, LTG, CBZ, or vehicle was administered intraperitoneally to fully kindled rats. Changes in Racine seizure score, after-discharge duration (ADD), and latency to Racine score 4 generalized seizure (SL) were measured to assess differences in the modes of seizure inhibition among the AEDs. Stimulation at 3xADT was used to eliminate the influence of any AED-induced elevation of the seizure threshold on these parameters.
PER, LEV, LCM, LTG, and CBZ significantly reduced the seizure score from Racine score 5 after stimulation at the ADT; this effect was lost with LEV and LTG after stimulation at 3xADT. PER and LEV significantly shortened the ADD when the seizure focus was stimulated at the ADT, whereas LCM, LTG, and CBZ did not. LEV, LCM, LTG, and CBZ failed to shorten the ADD upon stimulation at 3xADT. PER dose-dependently and significantly increased SL, even at doses that were ineffective for seizure score reduction, after stimulation at both the ADT and 3xADT. LEV and LTG significantly increased SL after stimulation at the ADT, whereas LCM and CBZ did not significantly increase SL at any of the doses tested.
The sodium channel blockers (LCM, LTG, and CBZ) appeared to act by elevation of the seizure threshold via reduction of neuronal excitability, whereas the AMPA receptor antagonist (PER) and the SV2A ligand (LEV), as well as LTG, exerted their effects through the weakening of synaptic transmission in neuronal networks at the seizure focus. Maintenance of the effect of PER even at 3xADT suggests direct and strong modulation of excitatory synaptic transmission by PER, both at the focus and along the seizure propagation route. These findings may provide further rationale for usage of AEDs beyond their respective modes of action.
有许多作用机制不同的抗癫痫药物（AEDs）对治疗局灶性发作有效。几种 AED，如吡仑帕奈（PER）、左乙拉西坦（LEV）、拉科酰胺（LCM）、拉莫三嗪（LTG）和卡马西平（CBZ），已被证明可在点燃模型中提高癫痫发作阈值。这些 AED 在临床上是有效的，但具有相似作用机制的药物在抗癫痫谱方面存在差异。因此，我们假设这些 AED 对癫痫发作的影响存在差异。在这里，我们通过在杏仁核点燃模型中以亚惊厥后放电阈值（ADT）和三倍 ADT（3xADT）刺激评估 AED 对各种癫痫发作参数的影响，以评估这些 AED 对不同癫痫发作参数的影响。
PER、LEV、LCM、LTG、CBZ 或载体通过腹膜内注射给予完全点燃的大鼠。测量 Racine 癫痫发作评分、后放电持续时间（ADD）和 Racine 评分 4 级全身性发作（SL）的潜伏期，以评估 AED 对癫痫发作抑制模式的差异。使用 3xADT 刺激消除任何 AED 诱导的癫痫发作阈值升高对这些参数的影响。
PER、LEV、LCM、LTG 和 CBZ 在 ADT 刺激时显著降低了 Racine 评分 5 后的癫痫发作评分；当刺激 3xADT 时，LEV 和 LTG 失去了这种作用。PER 和 LEV 在 ADT 刺激时显著缩短了 ADD，而 LCM、LTG 和 CBZ 则没有。LEV、LCM、LTG 和 CBZ 在 3xADT 刺激时未能缩短 ADD。PER 剂量依赖性地显著增加了 SL，即使在降低癫痫发作评分的无效剂量下，在 ADT 和 3xADT 刺激后均如此。LEV 和 LTG 在 ADT 刺激时显著增加了 SL，而 LCM 和 CBZ 在任何测试剂量下均未显著增加 SL。
钠通道阻滞剂（LCM、LTG 和 CBZ）似乎通过降低神经元兴奋性来通过提高癫痫发作阈值起作用，而 AMPA 受体拮抗剂（PER）和 SV2A 配体（LEV）以及 LTG 通过削弱癫痫发作焦点处的神经元网络中的突触传递来发挥作用。PER 甚至在 3xADT 时保持作用表明 PER 对兴奋性突触传递的直接和强烈调制，无论是在焦点处还是在癫痫传播途径中。这些发现可能为 AED 的使用提供了超出其各自作用机制的进一步依据。
