Department of Pharmacology and Chemical Biology, Emory University, 1510 Clifton Road NE, Atlanta, GA, 30322, United States.
Neuroscience Department, Medical Toxicology Research Division, United States Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Rd, Aberdeen Proving Ground, MD, 21010, United States.
Neurotoxicology. 2021 Mar;83:14-27. doi: 10.1016/j.neuro.2020.12.010. Epub 2020 Dec 19.
The increasing number of cases involving the use of nerve agents as deadly weapons has spurred investigation into the molecular mechanisms underlying nerve agent-induced pathology. The highly toxic nature of nerve agents restrict their use in academic research laboratories. Less toxic organophosphorus (OP) based agents including diisopropylfluorophosphate (DFP) are used as surrogates in academic research laboratories to mimic nerve agent poisoning. However, neuropathology resulting from DFP-induced status epilepticus (SE) has not been compared directly to neuropathology observed following nerve agent poisoning in the same study. Here, the hypothesis that neuropathology measured four days after SE is the same for rats exposed to DFP and soman was tested. Adult Sprague-Dawley rats were injected with soman or DFP to induce SE. Cortical electroencephalography (EEG) was recorded prior to and during soman-induced SE. EEG power analysis of rats administered soman revealed prolonged electrographic SE similar to that of rats that endure uninterrupted SE following injection of DFP. Rats that experienced soman-induced SE displayed less hippocampal neuroinflammation and gliosis compared to rats administered DFP. Seizure-induced weight change, blood-brain barrier (BBB) leakiness and neurodegeneration in most seizure sensitive limbic brain regions were similar for rats that endured SE following soman or DFP. The amalgamated pathology score calculated by combining pathological measures (weight loss, hippocampal neuroinflammation, gliosis, BBB integrity and neurodegeneration) was similar in rats administered the OP agents. These findings support use of the rat DFP model of SE as a suitable surrogate for investigating some, but not all delayed consequences produced by nerve agents.
随着使用神经毒剂作为致命武器的案例不断增加，人们对神经毒剂诱导的病理学的分子机制进行了深入研究。神经毒剂的高度毒性限制了它们在学术研究实验室中的使用。低毒有机磷（OP）类化合物，如二异丙基氟磷酸酯（DFP），被用作学术研究实验室中的替代品，以模拟神经毒剂中毒。然而，DFP 诱导的癫痫持续状态（SE）引起的神经病理学尚未与同一项研究中观察到的神经毒剂中毒引起的神经病理学进行直接比较。在这里，研究假设 SE 后 4 天测量的神经病理学对于暴露于 DFP 和梭曼的大鼠是相同的。成年 Sprague-Dawley 大鼠被注射梭曼或 DFP 以诱导 SE。在梭曼诱导的 SE 之前和期间记录皮质脑电图（EEG）。给予梭曼的大鼠的 EEG 功率分析显示出类似于连续接受 DFP 注射后发生的电描记 SE 的延长。与接受 DFP 治疗的大鼠相比，经历梭曼诱导 SE 的大鼠的海马神经炎症和神经胶质增生较少。与经历 SE 后接受梭曼或 DFP 的大鼠相比，癫痫诱导的体重变化、血脑屏障（BBB）通透性和大多数癫痫敏感的边缘脑区的神经退行性变相似。通过将病理测量值（体重减轻、海马神经炎症、神经胶质增生、BBB 完整性和神经退行性变）组合起来计算的综合病理评分，在接受 OP 药物治疗的大鼠中相似。这些发现支持使用大鼠 DFP SE 模型作为研究神经毒剂引起的一些但不是所有延迟后果的合适替代品。
