US Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, USA.
Toxicol Appl Pharmacol. 2012 Mar 15;259(3):376-86. doi: 10.1016/j.taap.2012.01.017. Epub 2012 Jan 30.
Therapy of seizure activity following exposure to the nerve agent soman (GD) includes treatment with the anticonvulsant diazepam (DZP), an allosteric modulator of γ-aminobutyric acid A (GABA(A)) receptors. However, seizure activity itself causes the endocytosis of GABA(A) receptors and diminishes the inhibitory effects of GABA, thereby reducing the efficacy of DZP. Treatment with an N-methyl-d-aspartic acid (NMDA) receptor antagonist prevents this reduction in GABAergic inhibition. We examined the efficacy of the NMDA receptor antagonist caramiphen edisylate (CED; 20mg/kg, im) and DZP (10mg/kg, sc), administered both separately and in combination, at 10, 20 or 30min following seizure onset for attenuation of the deleterious effects associated with GD exposure (1.2 LD(50); 132μg/kg, sc) in rats. Outcomes evaluated were seizure duration, neuropathology, acetylcholinesterase (AChE) activity, body weight, and temperature. We also examined the use of the reversible AChE inhibitor physostigmine (PHY; 0.2mg/kg, im) as a therapy for GD exposure. We found that the combination of CED and DZP yielded a synergistic effect, shortening seizure durations and reducing neuropathology compared to DZP alone, when treatment was delayed 20-30min after seizure onset. PHY reduced the number of animals that developed seizures, protected a fraction of AChE from GD inhibition, and attenuated post-exposure body weight and temperature loss independent of CED and/or DZP treatment. We conclude that: 1) CED and DZP treatment offers considerable protection against the effects of GD and 2) PHY is a potential therapeutic option following GD exposure, albeit with a limited window of opportunity.
暴露于神经毒剂沙林（GD）后，治疗惊厥发作的方法包括使用苯二氮䓬类药物（安定，DZP）进行治疗，DZP 是γ-氨基丁酸 A（GABA(A))受体的变构调节剂。然而，惊厥发作本身会导致 GABA(A)受体内吞，从而减弱 GABA 的抑制作用，降低 DZP 的疗效。使用 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂治疗可防止 GABA 能抑制作用的降低。我们研究了 NMDA 受体拮抗剂卡马西平乙二磺酸盐（CED；20mg/kg，肌内注射）和 DZP（10mg/kg，皮下注射）在惊厥发作后 10、20 或 30 分钟单独和联合给药，以减轻与 GD 暴露相关的有害影响（1.2 LD(50)；132μg/kg，皮下注射）在大鼠中的作用。评估的结果是惊厥持续时间、神经病理学、乙酰胆碱酯酶（AChE）活性、体重和体温。我们还研究了可逆 AChE 抑制剂毒扁豆碱（PHY；0.2mg/kg，肌内注射）作为 GD 暴露的治疗方法。我们发现，当治疗在惊厥发作后 20-30 分钟延迟时，CED 和 DZP 的联合使用产生了协同作用，与单独使用 DZP 相比，缩短了惊厥持续时间并减少了神经病理学变化。PHY 减少了发生惊厥的动物数量，保护了一部分 AChE 免受 GD 抑制，并减轻了暴露后体重和体温下降，而无需 CED 和/或 DZP 治疗。我们得出结论：1）CED 和 DZP 治疗对 GD 的影响提供了相当大的保护，2）PHY 是 GD 暴露后的一种潜在治疗选择，尽管机会有限。
