Chapman Shira, Yaakov Guy, Egoz Inbal, Rabinovitz Ishai, Raveh Lily, Kadar Tamar, Gilat Eran, Grauer Ettie
Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel.
Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel.
Neurotoxicology. 2015 Jul;49:132-8. doi: 10.1016/j.neuro.2015.05.001. Epub 2015 May 11.
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 μg/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 24h 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 1h (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 1mg/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.
沙林中毒的大鼠表现出高胆碱能活性，包括流涎过多、震颤、癫痫发作和死亡。在此，我们研究了咪达唑仑治疗对神经毒剂暴露后的时间和剂量效应。将大鼠暴露于沙林（1.2 LD50，108 μg/kg，腹腔注射），1分钟后用TMB4和阿托品（分别为7.5和5 mg/kg，腹腔注射）治疗。咪达唑仑在1分钟时（1 mg/kg，腹腔注射）或1小时后（1或5 mg/kg，肌肉注射）注射。通过脑电图（ECoG）监测皮层癫痫发作。在5周时，对大鼠进行水迷宫任务评估，然后提取它们的大脑进行生化分析和组织学评估。结果显示咪达唑仑治疗具有时间和剂量依赖性效应。仅用TA治疗的大鼠表现出沙林中毒的急性症状，29%在24小时内死亡，ECoG显示癫痫发作持续数小时。在1分钟内接受咪达唑仑治疗的动物存活下来，仅有轻微的临床症状，但没有生化、行为或组织学后遗症。在1小时时接受咪达唑仑治疗的存活动物（87%），延迟给药的效果具有剂量依赖性。5 mg/kg的咪达唑仑显著抵消了中毒的急性症状和行为表现受损，减轻了一些炎症反应，对形态学损伤无影响。1mg/kg的咪达唑仑仅显示出轻微调节认知功能的趋势。此外，与仅用TA治疗相比，两种剂量的咪达唑仑延迟给药均显著减弱了ECoG。这些结果表明，在长时间癫痫发作后，高剂量咪达唑仑有助于抵消沙林中毒的不良反应。
