Delayed midazolam dose effects against soman in male and female plasma carboxylesterase knockout mice,Annals of the New York Academy of Sciences

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Delayed midazolam dose effects against soman in male and female plasma carboxylesterase knockout mice
Annals of the New York Academy of Sciences ( IF 4.1 ) Pub Date : 2020-02-06 , DOI: 10.1111/nyas.14311
Erica Kundrick ₁ , Brenda Marrero-Rosado ₁ , Michael Stone ₁ , Caroline Schultz ₁ , Katie Walker ₁ , Robyn B Lee-Stubbs ₁ , Marcio de Araujo Furtado ₂ , Lucille A Lumley ₁

Affiliation

Chemical warfare nerve agent exposure leads to status epilepticus that may progress to epileptogenesis and severe brain pathology when benzodiazepine treatment is delayed. We evaluated the dose−response effects of delayed midazolam (MDZ) on toxicity induced by soman (GD) in the plasma carboxylesterase knockout (Es1−/−) mouse, which, similar to humans, lacks plasma carboxylesterase. Initially, we compared the median lethal dose (LD50) of GD exposure in female Es1−/− mice across estrous with male mice and observed a greater LD50 during estrus compared with proestrus or with males. Subsequently, male and female GD‐exposed Es1−/− mice treated with a dose range of MDZ 40 min after seizure onset were evaluated for survivability, seizure activity, and epileptogenesis. GD‐induced neuronal loss and microglial activation were evaluated 2 weeks after exposure. Similar to our previous observations in rats, delayed treatment with MDZ dose‐dependently increased survival and reduced seizure severity in GD‐exposed mice, but was unable to prevent epileptogenesis, neuronal loss, or gliosis. These results suggest that MDZ is beneficial against GD exposure, even when treatment is delayed, but that adjunct therapies to enhance protection need to be identified. The Es1−/− mouse GD exposure model may be useful to screen for improved medical countermeasures against nerve agent exposure.

中文翻译：

在雄性和雌性血浆羧酸酯酶敲除小鼠中咪达唑仑对梭曼的延迟剂量效应

化学战神经毒剂暴露会导致癫痫持续状态，当苯二氮卓类药物治疗延迟时，癫痫持续状态可能会发展为癫痫发生和严重的脑部病变。我们评估了延迟咪达唑仑 (MDZ) 对血浆羧酸酯酶敲除 (Es1-/-) 小鼠中梭曼 (GD) 诱导的毒性的剂量反应效应，该小鼠与人类相似，缺乏血浆羧酸酯酶。最初，我们比较了雌性 Es1-/- 小鼠在发情期间与雄性小鼠 GD 暴露的中位致死剂量 (LD50)，并观察到与发情前期或雄性相比，发情期间的 LD50 更大。随后，在癫痫发作后 40 分钟用 MDZ 剂量范围处理的雄性和雌性暴露于 GD 的 Es1-/- 小鼠进行了生存能力、癫痫发作活动和癫痫发生的评估。暴露后 2 周评估 GD 诱导的神经元丢失和小胶质细胞激活。与我们之前在大鼠中的观察结果相似，MDZ 延迟治疗剂量依赖性地增加了 GD 暴露小鼠的存活率并降低了癫痫发作的严重程度，但无法预防癫痫发生、神经元丢失或神经胶质增生。这些结果表明 MDZ 对 GD 暴露有益，即使治疗被延迟，但需要确定增强保护的辅助疗法。Es1-/- 小鼠 GD 暴露模型可能有助于筛选针对神经毒剂暴露的改进医学对策。这些结果表明 MDZ 对 GD 暴露有益，即使治疗被延迟，但需要确定增强保护的辅助疗法。Es1-/- 小鼠 GD 暴露模型可能有助于筛选针对神经毒剂暴露的改进医学对策。这些结果表明 MDZ 对 GD 暴露有益，即使治疗被延迟，但需要确定增强保护的辅助疗法。Es1-/- 小鼠 GD 暴露模型可能有助于筛选针对神经毒剂暴露的改进医学对策。

更新日期：2020-02-06

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