Rice A C, DeLorenzo R J
Department of Neurology, Virginia Commonwealth University, Richmond 23298-0599, USA.
Neuroscience. 1999;93(1):117-23. doi: 10.1016/s0306-4522(99)00132-3.
Status epilepticus, prolonged intermittent or continuous seizure activity lasting 30 min or longer, is associated with high morbidity and mortality. The longer a seizure persists, the more refractory to treatment it becomes. The pilocarpine model of status epilepticus in rodents develops refractoriness to many first-line treatments as seizure duration increases, rendering it a good model to study refractory status epilepticus. This study was initiated to study the development of refractoriness of pilocarpine-induced status epilepticus to diazepam. Early pilocarpine-induced status epilepticus responded rapidly to diazepam treatment, whereas status epilepticus of longer duration became increasingly less responsive to treatment. Dizocilpine maleate-pretreated animals responded rapidly to diazepam treatment, even after 60 min of status epilepticus. Animals administered dizocilpine maleate at 15, 30 or 60 min after the onset of status epilepticus also demonstrated a rapid response to diazepam compared to pilocarpine-alone-treated animals. The longer the status epilepticus progressed prior to dizocilpine maleate injection, the longer the status epilepticus lasted after diazepam treatment. However, in all cases where dizocilpine maleate was administered, one injection of diazepam was able to terminate the status epilepticus, in contrast to the animals that did not receive dizocilpine maleate, in which the seizure was only attenuated. The results indicate that N-methyl-D-aspartate receptor activation plays a role in the seizure-induced refractoriness to benzodiazepines in status epilepticus, and blocking N-methyl-D-aspartate receptor activation converts refractory status epilepticus to a seizure responsive to benzodiazepine therapy. These findings offer insights into developing novel therapeutic interventions to improve the treatment of status epilepticus. Understanding the molecular mechanisms that mediate the effects of N-methyl-D-aspartate receptor activation on the development of resistance to treatment in status epilepticus will provide rational insights into more rapid methods to terminate seizure activity in this condition.
癫痫持续状态是指持续30分钟或更长时间的长时间间歇性或持续性癫痫发作活动，与高发病率和死亡率相关。癫痫发作持续的时间越长，治疗就越难。随着癫痫发作持续时间的增加，啮齿动物癫痫持续状态的毛果芸香碱模型对许多一线治疗产生耐药性，使其成为研究难治性癫痫持续状态的良好模型。本研究旨在探讨毛果芸香碱诱导的癫痫持续状态对苯二氮䓬类药物耐药性的发展情况。早期毛果芸香碱诱导的癫痫持续状态对苯二氮䓬类药物治疗反应迅速，而持续时间较长的癫痫持续状态对治疗的反应越来越小。马来酸二氮嗪预处理的动物对苯二氮䓬类药物治疗反应迅速，即使在癫痫持续状态60分钟后也是如此。在癫痫持续状态发作后15、30或60分钟给予马来酸二氮嗪的动物与仅用毛果芸香碱治疗的动物相比，对苯二氮䓬类药物也表现出快速反应。在注射马来酸二氮嗪之前癫痫持续状态进展的时间越长，苯二氮䓬类药物治疗后癫痫持续状态持续的时间就越长。然而，在所有给予马来酸二氮嗪的情况下，一次注射苯二氮䓬类药物就能终止癫痫持续状态，与之形成对比的是未接受马来酸二氮嗪的动物，其癫痫发作仅得到缓解。结果表明，N-甲基-D-天冬氨酸受体激活在癫痫持续状态的癫痫发作诱导的对苯二氮䓬类药物耐药性中起作用，阻断N-甲基-D-天冬氨酸受体激活可将难治性癫痫持续状态转变为对苯二氮䓬类药物治疗有反应的癫痫发作。这些发现为开发新的治疗干预措施以改善癫痫持续状态的治疗提供了见解。了解介导N-甲基-D-天冬氨酸受体激活对癫痫持续状态治疗抵抗性发展影响的分子机制，将为在这种情况下更快速地终止癫痫发作活动的方法提供合理的见解。
