Nemes Ashley D, O'Dwyer Rebecca, Najm Imad M, Ying Zhong, Gonzalez-Martinez Jorge, Alexopoulos Andreas V
Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, U.S.A.
Department of Neurological Sciences, Rush Medical College, Chicago, Illinois, U.S.A.
Epilepsia. 2017 Oct;58(10):1755-1761. doi: 10.1111/epi.13856. Epub 2017 Aug 20.
Epilepsy is a common neurologic disorder resulting in spontaneous, recurrent seizures. About 30-40% of patients are not responsive to pharmacologic therapies. This may be due to the differences between individual patients such as etiology, underlying pathophysiology, and seizure focus, and it highlights the importance of new drug discovery and testing in this field. Our goal was to determine the efficacy of lacosamide (LCM), a drug approved for the treatment of focal seizures, in a model of generalized epilepsy with cortical dysplasia (CD). We sought to compare LCM to levetiracetam (LEV), a drug that is currently used for the treatment of both partial and generalized epilepsy and to test its proficiency.
Pregnant rats were irradiated to produce pups with malformed cortices in a model of CD, which will be referred to as the "first hit." Adult animals, developed normally (NL) and irradiated (XRT), were surgically implanted with electroencephalography (EEG) electrodes. Baseline EEG was recorded on all rats prior to pretreatments with either LCM, LEV, or placebo (PBO). After 30 min, all rats were injected with a subconvulsive dose of pentylenetetrazole (PTZ), a γ-aminobutyric acid receptor A (GABA ) antagonist used to provoke generalized seizures as a "second hit."
LCM and LEV were both effective against seizures induced by PTZ. XRT rats had a higher seizure incidence with longer and more severe seizures than NL rats. Seizure duration was decreased with both LCM and LEV in all animals. In XRT rats, there was a significant reduction in acute seizure incidence and severity with both LCM and LEV after PTZ injection.
Our results suggest that LCM could be used as a potential treatment option for generalized epilepsy with CD as the underlying pathology.
癫痫是一种常见的神经系统疾病，可导致自发性、反复发作的癫痫发作。约30%-40%的患者对药物治疗无反应。这可能是由于个体患者之间在病因、潜在病理生理学和癫痫发作灶等方面存在差异，这凸显了该领域新药研发和测试的重要性。我们的目标是确定已被批准用于治疗局灶性癫痫发作的拉科酰胺（LCM）在皮质发育异常（CD）所致全身性癫痫模型中的疗效。我们试图将LCM与左乙拉西坦（LEV）进行比较，LEV是目前用于治疗部分性和全身性癫痫的药物，并测试其效能。
对怀孕大鼠进行辐照，以在CD模型中产生皮质畸形的幼崽，这将被称为“首次打击”。正常发育（NL）和接受辐照（XRT）的成年动物通过手术植入脑电图（EEG）电极。在使用LCM、LEV或安慰剂（PBO）进行预处理之前，记录所有大鼠的基线脑电图。30分钟后，所有大鼠均注射亚惊厥剂量的戊四氮（PTZ），PTZ是一种γ-氨基丁酸A（GABA）受体拮抗剂，用于诱发全身性癫痫发作作为“二次打击”。
LCM和LEV均对PTZ诱发的癫痫发作有效。XRT大鼠的癫痫发作发生率高于NL大鼠，发作时间更长且更严重。所有动物使用LCM和LEV后癫痫发作持续时间均缩短。在XRT大鼠中，注射PTZ后，LCM和LEV均可显著降低急性癫痫发作的发生率和严重程度。
我们的结果表明，LCM可作为以CD为潜在病理基础的全身性癫痫的一种潜在治疗选择。
