Kulick Catherine V, Gutherz Samuel B, Beck Veronica C, Medvedeva Natalia, Soper Colin, Forcelli Patrick A
Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20007, USA.
Department of Pharmacology and Physiology, Georgetown University, Washington, DC 20007, USA; Interdisciplinary Program in Neuroscience, Georgetown University, School of Medicine, Washington, DC 20007, USA.
Eur J Pharmacol. 2014 Nov 15;743:63-8. doi: 10.1016/j.ejphar.2014.09.016. Epub 2014 Sep 22.
Levetiracetam (LEV) and tiagabine (TGB) are utilized for the treatment of seizures, including neonatal seizures. However, relatively little is known about the preclinical therapeutic profile of these drugs during brain development. The relative paucity of information regarding these drugs in neonatal animals may be due to their unusual profile of anticonvulsant action in experimental models. LEV and TGB are without effect against seizures in several common screening models (e.g., the maximal electroshock test, maximal pentylenetetrazole seizures), instead showing preferential efficacy against models of partial seizures. We have recently described a method for reliably evoking partial seizures in neonatal animals by systemic administration of the chemoconvulsant, DMCM (Kulick et al., 2014, Eur. J. Pharmacol., doi:10.1016/j.ejphar.2014.06.012). DMCM is a negative allosteric modulator of GABAA receptors, and offers a wide separation between doses required to evoke complex partial as compared to tonic-clonic seizures. Here we used DMCM to evaluate the effect of LEV and TGB against seizures in postnatal day (P) 10 rat pups. We compared the profile of LEV and TGB to that of phenobarbital (PB), the most widely utilized anticonvulsant in neonates. We found that LEV significantly protected against DMCM seizures when administered in doses of 10mg/kg and greater. TGB protected against DMCM-evoked seizures when administered in doses of 1mg/kg or greater. PB protected against DMCM-evoked seizures when administered in doses of 5mg/kg or greater. These data provide preclinical evidence for the efficacy of LEV and TGB in neonates and underscore the utility of DMCM for screening anticonvulsant action in neonatal animals.
左乙拉西坦（LEV）和噻加宾（TGB）用于治疗癫痫发作，包括新生儿癫痫。然而，对于这些药物在脑发育过程中的临床前治疗情况，人们了解得相对较少。关于这些药物在新生动物中的信息相对匮乏，可能是由于它们在实验模型中具有不同寻常的抗惊厥作用特征。LEV和TGB在几种常见的筛选模型（如最大电休克试验、最大戊四氮惊厥）中对癫痫发作无效，反而对部分性癫痫发作模型显示出优先疗效。我们最近描述了一种通过全身给予化学惊厥剂DMCM在新生动物中可靠诱发部分性癫痫发作的方法（Kulick等人，2014年，《欧洲药理学杂志》，doi:10.1016/j.ejphar.2014.06.012）。DMCM是GABAA受体的负变构调节剂，与诱发强直阵挛性癫痫发作所需的剂量相比，诱发复杂部分性癫痫发作所需的剂量有很大差异。在此，我们使用DMCM评估LEV和TGB对出生后第10天（P10）大鼠幼崽癫痫发作的影响。我们将LEV和TGB的情况与苯巴比妥（PB）进行了比较，苯巴比妥是新生儿中使用最广泛的抗惊厥药物。我们发现，当以10mg/kg及以上的剂量给药时，LEV能显著预防DMCM诱发的癫痫发作。当以1mg/kg及以上的剂量给药时，TGB能预防DMCM诱发的癫痫发作。当以5mg/kg及以上的剂量给药时，PB能预防DMCM诱发的癫痫发作。这些数据为LEV和TGB在新生儿中的疗效提供了临床前证据，并强调了DMCM在筛选新生动物抗惊厥作用方面的实用性。
