Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
Eur J Neurosci. 2010 Jul;32(1):80-8. doi: 10.1111/j.1460-9568.2010.07262.x. Epub 2010 Jun 28.
Status epilepticus is a clinical emergency that can lead to the development of acquired epilepsy following neuronal injury. Understanding the pathophysiological changes that occur between the injury itself and the expression of epilepsy is important in the development of new therapeutics to prevent epileptogenesis. Currently, no anti-epileptogenic agents exist; thus, the ability to treat an individual immediately after status epilepticus to prevent the ultimate development of epilepsy remains an important clinical challenge. In the Sprague-Dawley rat pilocarpine model of status epilepticus-induced acquired epilepsy, intracellular calcium has been shown to increase in hippocampal neurons during status epilepticus and remain elevated well past the duration of the injury in those animals that develop epilepsy. This study aimed to determine if such changes in calcium dynamics exist in the hippocampal culture model of status epilepticus-induced acquired epilepsy and, if so, to study whether manipulating the calcium plateau after status epilepticus would prevent epileptogenesis. The in vitro status epilepticus model resembled the in vivo model in terms of elevations in neuronal calcium concentrations that were maintained well past the duration of the injury. When used following in vitro status epilepticus, dantrolene, a ryanodine receptor inhibitor, but not the N-methyl-D-aspartic acid channel blocker MK-801 inhibited the elevations in intracellular calcium, decreased neuronal death and prevented the expression of spontaneous recurrent epileptiform discharges, the in vitro correlate of epilepsy. These findings offer potential for a novel treatment to prevent the development of epileptiform discharges following brain injuries.
癫痫持续状态是一种临床急症，可导致神经元损伤后继发性癫痫的发生。了解损伤本身和癫痫发作之间发生的病理生理变化，对于开发新的治疗方法以预防癫痫发生至关重要。目前尚无抗癫痫发生的药物；因此，能够在癫痫持续状态后立即治疗个体以预防最终发生癫痫仍然是一个重要的临床挑战。在匹罗卡品诱导的癫痫持续状态后获得性癫痫的 Sprague-Dawley 大鼠模型中，已经表明在癫痫持续状态期间海马神经元中的细胞内钙增加，并且在那些发生癫痫的动物中，这种增加持续超过损伤的持续时间。本研究旨在确定这种钙动力学变化是否存在于癫痫持续状态诱导的获得性癫痫的海马培养模型中，如果存在，研究是否可以通过操纵癫痫持续状态后的钙平台来预防癫痫发生。体外癫痫持续状态模型在神经元钙浓度升高方面与体内模型相似，这种升高持续时间远远超过损伤的持续时间。在体外癫痫持续状态后使用时，ryanodine 受体抑制剂丹曲林，但不是 N-甲基-D-天冬氨酸通道阻滞剂 MK-801，可抑制细胞内钙的升高，减少神经元死亡并防止自发性复发性癫痫样放电的表达，这是癫痫的体外相关物。这些发现为预防脑损伤后癫痫样放电的发生提供了一种新的治疗方法的潜力。
