Organophosphate (OP) compounds constitute a class of highly toxic molecules, characterized by irreversible cholinesterase (ChE) inhibition. Being either pesticides or chemical warfare agents, they present a major health issue in some countries, as well as a terrorist or military threat. Prompted by the need for suitable animal models to test novel medical countermeasures, we developed a new convulsive mouse model of OP poisoning using diisopropylfluorophosphate (DFP). Using electrocorticography (ECoG), we analyzed seizure and status epilepticus (SE) occurrences, as well as relative power of ECoG frequency band modifications after DFP injection in male Swiss mice. Next, we investigated DFP effect on ChE inhibition. Histological changes on neuronal activity and neuronal damage were examined by c‐Fos immunolabeling and Fluoro‐Jade C staining. We showed that mice exposed to DFP presented electrocorticographic seizures that rapidly progressed to SE within 20 minutes. Lasting >8 hours, DFP‐induced SE was associated with major power spectrum modifications in seizing DFP animals compared to control animals. Seizures and SE development were concomitant with profound ChE inhibition and induced massive neuronal degeneration. Presenting all hallmarks of convulsive OP poisoning, we showed that our mouse model is valuable for studying pathophysiological mechanisms and preclinical testing of newly available therapeutic molecules.

中文翻译：

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在二异丙基氟磷酸盐暴露的惊厥小鼠模型中有机磷酸盐诱导的脑损伤的表征

有机磷 (OP) 化合物构成一类剧毒分子，其特征是不可逆的胆碱酯酶 (ChE) 抑制。作为杀虫剂或化学战剂，它们在一些国家构成重大健康问题，以及恐怖主义或军事威胁。由于需要合适的动物模型来测试新的医疗对策，我们开发了一种使用二异丙基氟磷酸盐 (DFP) 的新型 OP 中毒惊厥小鼠模型。使用皮层电图 (ECoG)，我们分析了癫痫发作和癫痫持续状态 (SE) 的发生，以及在瑞士雄性小鼠中注射 DFP 后 ECoG 频带修改的相对功率。接下来，我们研究了 DFP 对 ChE 抑制的影响。通过 c-Fos 免疫标记和 Fluoro-Jade C 染色检查神经元活动和神经元损伤的组织学变化。我们发现，暴露于 DFP 的小鼠表现出脑电图癫痫发作，并在 20 分钟内迅速进展为 SE。持续 > 8 小时，与对照动物相比，DFP 诱导的 SE 与捕获 DFP 动物的主要功率谱改变有关。癫痫发作和 SE 发展伴随着严重的 ChE 抑制并诱导了大量的神经元变性。我们展示了抽搐 OP 中毒的所有特征，表明我们的小鼠模型对于研究病理生理机制和新可用治疗分子的临床前测试很有价值。癫痫发作和 SE 发展伴随着严重的 ChE 抑制并诱导了大量的神经元变性。我们展示了抽搐 OP 中毒的所有特征，表明我们的小鼠模型对于研究病理生理机制和新可用治疗分子的临床前测试很有价值。癫痫发作和 SE 发展伴随着严重的 ChE 抑制并诱导了大量的神经元变性。我们展示了抽搐 OP 中毒的所有特征，表明我们的小鼠模型对于研究病理生理机制和新可用治疗分子的临床前测试很有价值。