Medical Toxicology Research Division, Neuroscience Department, U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010, USA.
Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.
Neuroscience. 2020 Jan 15;425:280-300. doi: 10.1016/j.neuroscience.2019.11.020. Epub 2019 Nov 26.
Organophosphorus (OP) compounds are deadly chemicals that exert their intoxicating effects through the irreversible inhibition of acetylcholinesterase (AChE). In addition to an excess of peripheral ailments, OP intoxication induces status epilepticus (SE) which if left untreated may lead to permanent brain damage or death. Benzodiazepines are typically the primary therapies for OP-induced SE, but these drugs lose efficacy as treatment time is delayed. The CounterACT Neurotherapeutic Screening (CNS) Program was therefore established by the National Institutes of Health (NIH) to discover novel treatments that may be administered adjunctively with the currently approved medical countermeasures for OP-induced SE in a delayed treatment scenario. The CNS program utilizes in vivo EEG recordings and Fluoro-JadeB (FJB) histopathology in two established rat models of OP-induced SE, soman (GD) and diisopropylfluorophosphate (DFP), to evaluate the anticonvulsant and neuroprotectant efficacy of novel adjunct therapies when administered at 20 or 60 min after the induction of OP-induced SE. Here we report the results of multiple compounds that have previously shown anticonvulsant or neuroprotectant efficacy in other models of epilepsy or trauma. Drugs tested were ganaxolone, diazoxide, bumetanide, propylparaben, citicoline, MDL-28170, and chloroquine. EEG analysis revealed that ganaxolone demonstrated the most robust anticonvulsant activity, whereas all other drugs failed to attenuate ictal activity in both models of OP-induced SE. FJB staining demonstrated that none of the tested drugs had widespread neuroprotective abilities. Overall these data suggest that neurosteroids may represent the most promising anticonvulsant option for OP-induced SE out of the seven unique mechanisms tested here. Additionally, these results suggest that drugs that provide significant neuroprotection from OP-induced SE without some degree of anticonvulsant activity are elusive, which further highlights the necessity to continue screening novel adjunct treatments through the CNS program.
有机磷（OP）化合物是致命的化学物质，通过不可逆地抑制乙酰胆碱酯酶（AChE）发挥其中毒作用。除了过多的外周疾病外，OP 中毒还会引起癫痫持续状态（SE），如果不治疗，可能会导致永久性脑损伤或死亡。苯二氮䓬类药物通常是治疗 OP 诱导的 SE 的主要药物，但随着治疗时间的延迟，这些药物的疗效会降低。因此，美国国立卫生研究院（NIH）建立了 CounterACT 神经治疗筛选（CNS）计划，以发现可能与目前批准的用于 OP 诱导 SE 的医疗对策联合使用的新疗法，以在延迟治疗情况下治疗 OP 诱导的 SE。该 CNS 计划利用体内 EEG 记录和 Fluoro-JadeB（FJB）组织病理学，在两种已建立的 OP 诱导 SE 大鼠模型，即梭曼（GD）和二异丙基氟磷酸酯（DFP）中，评估新型辅助治疗在 OP 诱导 SE 后 20 或 60 分钟给药时的抗惊厥和神经保护疗效。在这里，我们报告了先前在其他癫痫或创伤模型中显示出抗惊厥或神经保护作用的多种化合物的结果。测试的药物有 ganaxolone、diazoxide、bumetanide、propylparaben、citicoline、MDL-28170 和氯喹。EEG 分析表明，ganaxolone 表现出最强大的抗惊厥活性，而其他所有药物都未能减轻两种 OP 诱导 SE 模型中的癫痫发作活动。FJB 染色表明，测试的药物均没有广泛的神经保护能力。总的来说，这些数据表明，神经甾体可能是这里测试的七种独特机制中最有希望的治疗 OP 诱导 SE 的药物。此外，这些结果表明，提供 OP 诱导 SE 神经保护而没有一定程度抗惊厥活性的药物是难以捉摸的，这进一步强调了通过 CNS 计划继续筛选新型辅助治疗的必要性。
