Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, 1089 Veterinary Medicine Drive, Davis, CA, 95616, USA.
Department of Public Health Sciences, University of California-Davis, One Shields Avenue, Davis, CA, 95616, USA.
Neurotoxicology. 2019 Jul;73:81-84. doi: 10.1016/j.neuro.2019.03.001. Epub 2019 Mar 7.
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.
急性有机磷酯类胆碱酯酶抑制剂（OPs）中毒是对人类健康的重大威胁，目前针对 OP 中毒的医学对策疗效有限。二异丙基氟磷酸酯（DFP）急性中毒的大鼠模型越来越多地被用于测试候选化合物在预防急性 OP 毒性的即时和长期后果方面的疗效。在该模型中，通常用溴化吡斯的明（PB）预处理大鼠，这是一种可逆的胆碱酯酶抑制剂，以提高存活率。然而，在大多数平民接触到急性神经毒性水平 OPs 的情况下，PB 预处理不太可能发生。因此，本研究的目的是确定 PB 预处理是否会显著提高 DFP 中毒大鼠的存活率。成年雄性 Sprague Dawley 大鼠皮下注射 DFP（4mg/kg）或载体（VEH），1 分钟后，同时肌内注射硫酸阿托品（2mg/kg）和 2-派洛肟（25mg/kg）。这些注射前 30 分钟，动物用 PB（0.1mg/kg，肌内注射）或等量生理盐水预处理。DFP 引发快速且持续的癫痫发作行为，与 PB 预处理无关，并且在注射后 4 小时内，PB 预处理或未预处理的 DFP 动物的平均癫痫发作行为评分没有显著差异。PB 预处理对 24 小时后 DFP 暴露后的生存或大脑 AChE 活性也没有显著影响。综上所述，在 DFP 急性中毒的大鼠模型中，PB 预处理不是确保大鼠存活所必需的，并且在急性 DFP 中毒的大鼠模型中消除 PB 预处理会增加其与平民急性 OP 中毒的相关性。
