N-methyl-D-aspartate receptor activation regulates refractoriness of status epilepticus to diazepam
N-methyl-D-aspartate receptor activation regulates refractoriness of status epilepticus to diazepam
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DOI：
10.1016/s0306-4522(99)00132-3
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发表时间：
1999-01-01
期刊：
影响因子：
3.3
通讯作者：
DeLorenzo, RJ
中科院分区：
文献类型：
--
作者：
Rice, AC;DeLorenzo, RJ
癫痫持续状态，即持续30分钟或更长时间的间歇或持续发作活动，与高发病率和高死亡率有关，发作持续时间越长，越难以治疗。随着癫痫持续时间的延长，匹罗卡品在啮齿类动物癫痫持续状态模型中对许多一线治疗产生耐受性，使其成为研究难治性癫痫持续状态的良好模型。本研究旨在研究匹罗卡品诱导的癫痫持续状态对安定的耐受性。早期匹罗卡品诱发的癫痫持续状态对安定治疗反应迅速，而持续时间较长的癫痫持续状态对治疗的反应越来越差。即使在癫痫持续状态60分钟后，经马来酸地佐西平预处理的动物对安定治疗的反应也很快。与匹罗卡品单独治疗的动物相比，在癫痫持续状态发生后15分钟、30分钟或60分钟给予马来酸地佐西平的动物也显示出对安定的快速反应。注射马来酸地佐西平前癫痫持续时间越长，安定治疗后癫痫持续时间越长。然而，在所有接受马来酸地佐西平治疗的动物中，一次注射安定就能够终止癫痫持续状态，而没有接受马来酸地佐西平治疗的动物，癫痫发作只是减轻了。结果表明，N-甲基-D-天冬氨酸受体激活在癫痫持续状态发作诱导的苯二氮卓类药物难治性发作中起一定作用，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化为对苯二氮卓类药物治疗有效的癫痫发作。这些发现为开发新的治疗措施以提高癫痫持续状态的治疗水平提供了启示。了解N-甲基-D-天冬氨酸受体激活在癫痫持续状态抵抗形成中的作用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提供合理的见解。(C)1999年IBRO。爱思唯尔科学有限公司出版。
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. (C) 1999 IBRO. Published by Elsevier Science Ltd.