Current medical countermeasures for organophosphate (OP)-induced status epilepticus (SE) are not effective in preventing long-term morbidity and there is an urgent need for improved therapies. Rat models of acute intoxication with the OP, diisopropylfluorophosphate (DFP), are increasingly being used to evaluate therapeutic candidates for efficacy in mitigating the long-term neurologic effects associated with OP-induced SE. Many of these therapeutic candidates target neuroinflammation and oxidative stress because of their implication in the pathogenesis of persistent neurologic deficits associated with OP-induced SE. Critical to these efforts is the rigorous characterization of the rat DFP model with respect to outcomes associated with acute OP intoxication in humans, which include long-term electroencephalographic, neurobehavioral, and neuropathologic effects, and their temporal relationship to neuroinflammation and oxidative stress. To address these needs, we examined a range of outcomes at later times post-exposure than have previously been reported for this model. Adult male Sprague-Dawley rats were given pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), which was immediately followed by atropine sulfate (2 mg/kg, im) and pralidoxime (25 mg/kg, im). This exposure paradigm triggered robust electroencephalographic and behavioral seizures that rapidly progressed to SE lasting several hours in 90% of exposed animals. Animals that survived DFP-induced SE (~70%) exhibited spontaneous recurrent seizures and hyperreactive responses to tactile stimuli over the first 2 months post-exposure. Performance in the elevated plus maze, open field, and Pavlovian fear conditioning tests indicated that acute DFP intoxication reduced anxiety-like behavior and impaired learning and memory at 1 and 2 months post-exposure in the absence of effects on general locomotor behavior. Immunohistochemical analyses revealed significantly increased expression of biomarkers of reactive astrogliosis, microglial activation and oxidative stress in multiple brain regions at 1 and 2 months post-DFP, although there was significant spatiotemporal heterogeneity across these endpoints. Collectively, these data largely support the relevance of the rat model of acute DFP intoxication as a model for acute OP intoxication in the human, and support the hypothesis that neuroinflammation and/or oxidative stress represent potential therapeutic targets for mitigating the long-term neurologic sequelae of acute OP intoxication.

中文翻译：

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在急性有机磷酸盐中毒的大鼠模型中，持续的行为缺陷，神经炎症和氧化应激。

对于有机磷酸酯（OP）引起的癫痫持续状态（SE）的当前医学对策不能有效地预防长期发病，因此迫切需要改进疗法。OP急性中毒的大鼠模型，二异丙基氟磷酸酯（DFP）被越来越多地用于评估治疗候选物缓解与OP诱导的SE相关的长期神经系统功效的功效。这些治疗候选物中的许多靶向神经发炎和氧化应激，因为它们暗示了与OP诱导的SE相关的持续性神经功能缺损的发病机理。对于这些努力而言，至关重要的是，针对与人急性OP中毒有关的结局，严格刻画大鼠DFP模型，包括长期的脑电图，神经行为，和神经病理作用，以及它们与神经炎症和氧化应激的时间关系。为了满足这些需求，我们在暴露后的时间比该模型先前报道的时间范围内检查了一系列结果。成年雄性Sprague-Dawley大鼠在施用DFP（4 mg / kg，皮下注射）之前30分钟接受吡tig斯的明溴（0.1 mg / kg，皮下注射），随后立即给予硫酸阿托品（2 mg / kg，皮下注射）和普利肟（25 mg / kg，im）。这种暴露范例触发了强劲的脑电图和行为癫痫发作，在90％的暴露动物中迅速发展为SE，持续数小时。在暴露后的前两个月内，DFP诱导的SE（〜70％）存活的动物表现出自发性反复发作和对触觉刺激的高反应性反应。在高架迷宫，开阔野外的表现，和帕夫洛夫（Pavlovian）恐惧条件测试表明，急性DFP中毒在暴露后1个月和2个月时减少了焦虑样行为，并损害了学习和记忆，而对一般运动行为没有影响。免疫组织化学分析显示，DFP后1和2个月，多个脑区的反应性星形胶质细胞增生，小胶质细胞活化和氧化应激的生物标志物表达显着增加，尽管这些终点之间存在显着的时空异质性。总的来说，这些数据在很大程度上支持了大鼠急性DFP中毒作为人类急性OP中毒的模型的相关性，并支持了神经炎症和/或氧化应激代表减轻长期神经系统后遗症的潜在治疗靶点的假设。急性OP中毒。