Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah.
Epilepsy Therapy Screening Program (ETSP) Contract Site, University of Utah, Salt Lake City, Utah.
Epilepsia. 2018 Nov;59(11):2035-2048. doi: 10.1111/epi.14563. Epub 2018 Oct 17.
Approximately 30% of patients with epilepsy are refractory to existing antiseizure drugs (ASDs). Given that the properties of the central nervous systems of these patients are likely to be altered due to their epilepsy, tissues from rodents that have undergone epileptogenesis might provide a therapeutically relevant disease substrate for identifying compounds capable of attenuating pharmacoresistant seizures. To facilitate the development of such a model, this study describes the effects of classical glutamate receptor antagonists and 20 ASDs on recurrent epileptiform discharges (REDs) in brain slices derived from the kainate-induced status epilepticus model of temporal lobe epilepsy (KA-rats).
Horizontal brain slices containing the medial entorhinal cortex (mEC) were prepared from KA-rats, and REDs were recorded from the superficial layers. 6-cyano-7-nitroquinoxaline-2,3-dione, (2R)-amino-5-phosphonovaleric acid, tetrodotoxin, or ASDs were bath applied for 20 minutes. Concentration-dependent effects and half maximal effective concentration values were determined for RED duration, frequency, and amplitude.
ASDs targeting sodium and potassium channels (carbamazepine, eslicarbazepine, ezogabine, lamotrigine, lacosamide, phenytoin, and rufinamide) attenuated REDs at concentrations near their average therapeutic plasma concentrations. γ-aminobutyric acid (GABA)ergic synaptic transmission-modulating ASDs (clobazam, midazolam, phenobarbital, stiripentol, tiagabine, and vigabatrin) attenuated REDs only at higher concentrations and, in some cases, prolonged RED durations. ASDs with other/mixed mechanisms of action (bumetanide, ethosuximide, felbamate, gabapentin, levetiracetam, topiramate, and valproate) and glutamate receptor antagonists weakly or incompletely inhibited RED frequency, increased RED duration, or had no significant effects.
Taken together, these data suggest that epileptiform activity recorded from the superficial layers of the mEC in slices obtained from KA-rats is differentially sensitive to existing ASDs. The different sensitivities of REDs to these ASDs may reflect persistent molecular, cellular, and/or network-level changes resulting from disease. These data are expected to serve as a foundation upon which future therapeutics may be differentiated and assessed for potentially translatable efficacy in patients with refractory epilepsy.
约 30%的癫痫患者对现有抗癫痫药物（ASD）耐药。鉴于这些患者的中枢神经系统特性可能因癫痫而改变，因此接受过癫痫发生的啮齿动物组织可能为鉴定能够减轻耐药性癫痫发作的化合物提供具有治疗相关性的疾病基础。为了促进此类模型的发展，本研究描述了经典谷氨酸受体拮抗剂和 20 种 ASD 对源自海人酸诱导的颞叶癫痫（KA-大鼠）癫痫持续状态模型的脑切片中复发性癫痫样放电（REDs）的影响。
从 KA-大鼠中制备包含内侧嗅皮层（mEC）的水平脑切片，并从浅层记录 REDs。6-氰基-7-硝基喹喔啉-2,3-二酮、（2R）-氨基-5-膦戊酸、河豚毒素或 ASD 经浴给药 20 分钟。确定 RED 持续时间、频率和幅度的浓度依赖性效应和半最大有效浓度值。
针对钠和钾通道的 ASD（卡马西平、依佐加滨、埃索加滨、拉莫三嗪、左乙拉西坦、苯妥英和鲁非酰胺）在接近其平均治疗血浆浓度的浓度下减轻 RED。γ-氨基丁酸（GABA）能突触传递调节 ASD（氯巴占、咪达唑仑、苯巴比妥、司替戊醇、噻加宾和维加特林）仅在较高浓度下减轻 RED，并在某些情况下延长 RED 持续时间。具有其他/混合作用机制的 ASD（布美他尼、乙琥胺、非尔氨酯、加巴喷丁、左乙拉西坦、托吡酯和丙戊酸）和谷氨酸受体拮抗剂对 RED 频率的抑制作用较弱或不完全，增加 RED 持续时间，或无显著影响。
综上所述，这些数据表明，从 KA-大鼠获得的脑切片浅层记录的癫痫样活动对现有的 ASD 具有不同的敏感性。RED 对这些 ASD 的不同敏感性可能反映了疾病引起的持续的分子、细胞和/或网络水平的变化。这些数据有望成为未来治疗药物的基础，以便对难治性癫痫患者的潜在转化疗效进行区分和评估。
