The Limitations of Diazepam as a Treatment for Nerve Agent-Induced Seizures and Neuropathology in Rats: Comparison with UBP302
The Limitations of Diazepam as a Treatment for Nerve Agent-Induced Seizures and Neuropathology in Rats: Comparison with UBP302
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DOI：
10.1124/jpet.114.217299
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发表时间：
2014-11-01
影响因子：
3.5
通讯作者：
Braga, Maria F. M.
中科院分区：
文献类型：
--
作者：
Apland, James P.;Aroniadou-Anderjaska, Vassiliki;Braga, Maria F. M.
暴露于神经毒剂会引起长时间的癫痫持续状态（SE），导致脑损伤或死亡。地西泮（DZP）是目前美国食品和药物管理局批准的用于停止神经毒剂诱导的SE的药物。在这里，我们比较了DZP与UBP302 [(S)-3-（2-羧基苄基）威地啶]的疗效；一种含有GluK1亚基的盐酸盐受体拮抗剂，可在大鼠中抗由人类引起的癫痫发作、神经病理和行为缺陷。暴露后1小时或2小时给予DZP，终止SE，但癫痫发作复发；因此，索曼暴露后24小时内SE的总持续时间与未服用抗惊厥药的索曼暴露大鼠相似（1小时时DZP）或长于（2小时时DZP）。与DZP相比，UBP302停止SE的时间过程较慢，但显著缩短了SE在24小时内的总持续时间。在暴露后1小时接受抗惊厥药物治疗的组进行神经病理学和行为评估。UBP302，而不是DZP，减少了许多脑区域的神经元变性，以及基底外侧杏仁核和CA1海马区的神经元丢失，并防止了基底外侧杏仁核的神经元间丢失。在人类暴露30天后，在野外和通过声惊吓反应评估焦虑样行为。结果显示，dzp治疗组和未接受抗惊厥药物治疗组的焦虑样行为增加，但ubp302治疗组没有增加。研究结果反对使用DZP治疗神经毒剂引起的癫痫发作和脑损伤，并建议靶向含gluk1受体是一种更有效的方法。
Exposure to nerve agents induces prolonged status epilepticus (SE), causing brain damage or death. Diazepam (DZP) is the current US Food and Drug Administration-approved drug for the cessation of nerve agent-induced SE. Here, we compared the efficacy of DZP with that of UBP302 [(S)-3-(2-carboxybenzyl) willardiine; an antagonist of the kainate receptors that contain the GluK1 subunit] against seizures, neuropathology, and behavioral deficits induced by soman in rats. DZP, administered 1 hour or 2 hours postexposure, terminated the SE, but seizures returned; thus, the total duration of SE within 24 hours after soman exposure was similar to (DZP at 1 hour) or longer than (DZP at 2 hours) that in the soman-exposed rats that did not receive the anticonvulsant. Compared with DZP, UBP302 stopped SE with a slower time course, but dramatically reduced the total duration of SE within 24 hours. Neuropathology and behavior were assessed in the groups that received anticonvulsant treatment 1 hour after exposure. UBP302, but not DZP, reduced neuronal degeneration in a number of brain regions, as well as neuronal loss in the basolateral amygdala and the CA1 hippocampal area, and prevented interneuronal loss in the basolateral amygdala. Anxiety-like behavior was assessed in the open field and by the acoustic startle response 30 days after soman exposure. The results showed that anxiety-like behavior was increased in the DZP-treated group and in the group that did not receive anticonvulsant treatment, but not in the UBP302-treated group. The results argue against the use of DZP for the treatment of nerve agent-induced seizures and brain damage and suggest that targeting GluK1-containing receptors is a more effective approach.