Sarin-induced brain damage in rats is attenuated by delayed administration of midazolam
Sarin-induced brain damage in rats is attenuated by delayed administration of midazolam
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DOI：
10.1016/j.neuro.2015.05.001
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发表时间：
2015-07-01
期刊：
影响因子：
3.4
通讯作者：
Grauer, Ettie
中科院分区：
文献类型：
--
作者：
Chapman, Shira;Yaakov, Guy;Grauer, Ettie
沙林中毒的老鼠表现出高胆碱能活动，包括唾液分泌过多、震颤、癫痫发作和死亡。在这里，我们研究了神经毒剂暴露后咪达唑仑治疗的时间和剂量效应。大鼠暴露于沙林（1.2 LD50，108 μg/kg，肌肉注射），1 分钟后用 TMB4 和阿托品（TA 7.5 和 5 mg/kg，肌肉注射）治疗。咪达唑仑在 1 分钟（1 mg/kg，肌肉注射）或 1 小时后（1 或 5 mg/kg，肌肉注射）注射。通过皮质电图（ECoG）监测皮质癫痫发作。 5周时，对大鼠进行水迷宫任务评估，然后提取其大脑进行生化分析和组织学评估。结果显示咪达唑仑治疗的效果具有时间和剂量依赖性。接受 TA 治疗的大鼠仅表现出沙林中毒的急性症状，29% 的大鼠在 24 小时内死亡，ECoG 显示癫痫发作持续数小时。 1 分钟内接受咪达唑仑治疗的动物仅出现轻微临床症状，但没有生化、行为或组织学后遗症。 1 小时后接受咪达唑仑治疗的动物 (87%) 存活下来，并且延迟给药的效果是剂量依赖性的。咪达唑仑 5 mg/kg 可显着抵消急性中毒症状和行为表现受损，减轻部分炎症反应，但对形态损伤没有影响。咪达唑仑 I mg/kg 仅表现出轻微的调节认知功能的倾向。此外，与仅 TA 治疗相比，两种咪达唑仑剂量的延迟给药均显着减弱了 ECoG。这些结果表明，长期癫痫发作后，高剂量咪达唑仑有利于抵消沙林中毒的不良反应。 (C) 2015 Elsevier Inc. 保留所有权利。
Sarin poisoned rats display a hyper-cholinergic activity including hypersalivation, tremors, seizures and death. Here we studied the time and dose effects of midazolam treatment following nerve agent exposure. Rats were exposed to sarin (1.2 LD50, 108 mu g/kg, im), and treated 1 min later with TMB4 and atropine (TA 7.5 and 5 mg/kg, im, respectively). Midazolam was injected either at 1 min (1 mg/kg, im), or 1 h later (1 or 5 mg/kg i.m.). Cortical seizures were monitored by electrocorticogram (ECoG). At 5 weeks, rats were assessed in a water maze task, and then their brains were extracted for biochemical analysis and histological evaluation. Results revealed a time and dose dependent effects of midazolam treatment. Rats treated with TA only displayed acute signs of sarin intoxication, 29% died within 24 h and the ECoG showed seizures for several hours. Animals that received midazolam within 1 min survived with only minor clinical signs but with no biochemical, behavioral, or histological sequel. Animals that lived to receive midazolam at 1 h (87%) survived and the effects of the delayed administration were dose dependent. Midazolam 5 mg/kg significantly counteracted the acute signs of intoxication and the impaired behavioral performance, attenuated some of the inflammatory response with no effect on morphological damage. Midazolam I mg/kg showed only a slight tendency to modulate the cognitive function. In addition, the delayed administration of both midazolam doses significantly attenuated ECoG compared to TA treatment only. These results suggest that following prolonged seizure, high dose midazolam is beneficial in counteracting adverse effects of sarin poisoning. (C) 2015 Elsevier Inc. All rights reserved.