Pretreatment with pyridostigmine bromide has no effect on seizure behavior or 24 hour survival in the rat model of acute diisopropylfluorophosphate intoxication
Pretreatment with pyridostigmine bromide has no effect on seizure behavior or 24 hour survival in the rat model of acute diisopropylfluorophosphate intoxication
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DOI：
10.1016/j.neuro.2019.03.001
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发表时间：
2019-07-01
期刊：
影响因子：
3.4
通讯作者：
Lein, Pamela J.
中科院分区：
文献类型：
--
作者：
Bruun, Donald A.;Guignet, Michelle;Lein, Pamela J.
急性有机磷胆碱酯酶抑制剂中毒是一种严重威胁人类健康的药物，目前的药物治疗效果有限。用二异丙基氟磷酸盐（DFP）急性中毒的大鼠模型越来越多地用于测试候选化合物在保护免受急性OP毒性的立即和长期后果方面的功效。在该模型中，通常用溴化吡啶斯的明（PB）（一种可逆的胆碱酯酶抑制剂）预处理大鼠，以提高存活率。然而，PB预处理是不可能在大多数情况下，平民接触急性神经毒性水平的OP。因此，本研究的目的是确定PB预处理是否显著增加DFP中毒大鼠的存活率。将成年雄性Sprague道利大鼠用DFP（4 mg/kg，s.c.）或媒介物（VEH），随后1分钟后通过联合i.m.注射硫酸阿托品（2 mg/kg）和2-解磷定（25 mg/kg）。或者等体积的生理盐水无论PB预处理与否，DFP均触发快速和持续的癫痫发作行为，并且在注射后的前4 h内，PB预处理或未预处理的DFP动物之间的平均癫痫发作行为评分无显著差异。PB预处理也没有显着影响的生存或脑AChE活性在24小时后DFP曝光。总之，PB预处理对于确保DFP急性中毒大鼠的存活是不必要的，并且在急性DFP中毒大鼠模型中消除PB预处理将增加其与平民急性OP中毒的相关性。
Acute intoxication with organophosphate cholinesterase inhibitors (OPs) is a significant human health threat, and current medical countermeasures for OP poisoning are of limited therapeutic efficacy. The rat model of acute intoxication with diisopropylfluorophosphate (DFP) is increasingly being used to test candidate compounds for efficacy in protecting against the immediate and long-term consequences of acute OP toxicity. In this model, rats are typically pretreated with pyridostigmine bromide (PB), a reversible cholinesterase inhibitor, to enhance survival. However, PB pretreatment is not likely in most scenarios of civilian exposure to acutely neurotoxic levels of OPs. Therefore, the goal of this study was to determine whether PB pretreatment significantly increases survival in DFP-intoxicated rats. Adult male Sprague Dawley rats were injected with DFP (4 mg/kg, s.c.) or vehicle (VEH) followed 1 min later by combined i.m. injection of atropine sulfate (2 mg/kg) and 2-pralidoxime (25 mg/kg), Animals were pretreated 30 min prior to these injections with PB (0.1 mg/kg, i.m.) or an equal volume of saline. DFP triggered rapid and sustained seizure behavior irrespective of PB pretreatment, and there was no significant difference in average seizure behavior score during the first 4 h following injection between DFP animals pretreated with PB or not. PB pretreatment also had no significant effect on survival or brain AChE activity at 24 h post-DFP exposure. In summary, PB pretreatment is not necessary to ensure survival of rats acutely intoxicated with DFP, and eliminating PB pretreatment in the rat model of acute DFP intoxication would increase its relevance to acute OP intoxication in civilians.