Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center College of Medicine, Bryan, Texas.
Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center College of Medicine, Bryan, Texas
J Pharmacol Exp Ther. 2018 Nov;367(2):302-321. doi: 10.1124/jpet.117.247106. Epub 2018 Aug 16.
Organophosphates (OP) such as the pesticide diisopropylfluorophosphate (DFP) and the nerve agent sarin are lethal chemicals that induce seizures, status epilepticus (SE), and brain damage. Midazolam, a benzodiazepine modulator of synaptic GABA-A receptors, is currently considered as a new anticonvulsant for nerve agents. Here, we characterized the time course of protective efficacy of midazolam (0.2-5 mg/kg, i.m.) in rats exposed to DFP, a chemical threat agent and surrogate for nerve agents. Behavioral and electroencephalogram (EEG) seizures were monitored for 24 hours after DFP exposure. The extent of brain injury was determined 3 days after DFP exposure by unbiased stereologic analyses of valid markers of neurodegeneration and neuroinflammation. Seizures were elicited within ∼8 minutes after DFP exposure that progressively developed into persistent SE lasting for hours. DFP exposure resulted in massive neuronal injury or necrosis, neurodegeneration of principal cells and interneurons, and neuroinflammation as evident by extensive activation of microglia and astrocytes in the hippocampus, amygdala, and other brain regions. Midazolam controlled seizures, neurodegeneration, and neuroinflammation when given early (10 minutes) after DFP exposure, but it was less effective when given at 40 minutes or later. Delayed therapy (≥40 minutes), a simulation of the practical therapeutic window for first responders or hospital admission, was associated with reduced seizure protection and neuroprotection. These results strongly reaffirm that the DFP-induced seizures and brain damage are progressively resistant to delayed treatment with midazolam, confirming the benzodiazepine refractory SE after OP intoxication. Thus, novel anticonvulsants superior to midazolam or adjunct therapies that enhance its efficacy are needed for effective treatment of refractory SE.
有机磷化合物（OP），如杀虫剂二异丙基氟膦（DFP）和神经毒剂沙林，是致命的化学物质，可引发癫痫发作、癫痫持续状态（SE）和脑损伤。咪达唑仑是一种苯二氮䓬类药物，可调节突触 GABA-A 受体，目前被认为是一种治疗神经毒剂的新型抗惊厥药物。在这里，我们描述了咪达唑仑（0.2-5mg/kg，肌内注射）在接触 DFP（化学威胁剂和神经毒剂替代品）的大鼠中的保护作用的时间过程。在 DFP 暴露后 24 小时内监测行为和脑电图（EEG）发作。在 DFP 暴露后 3 天，通过对神经退行性和神经炎症的有效标志物进行无偏立体学分析，确定脑损伤程度。DFP 暴露后约 8 分钟内引发癫痫发作，逐渐发展为持续数小时的 SE。DFP 暴露导致大量神经元损伤或坏死、主要细胞和中间神经元的神经退行性变以及神经炎症，如海马、杏仁核和其他脑区的小胶质细胞和星形胶质细胞广泛激活。咪达唑仑在 DFP 暴露后 10 分钟内早期给药可控制癫痫发作、神经退行性变和神经炎症，但在 40 分钟后给药效果较差。延迟治疗（≥40 分钟），模拟急救人员或入院的实际治疗窗口，与减少癫痫发作保护和神经保护相关。这些结果强烈证实，咪达唑仑延迟治疗可使 DFP 诱导的癫痫发作和脑损伤逐渐对其产生耐药性，证实了有机磷化合物中毒后苯二氮䓬类难治性 SE。因此，需要新型抗惊厥药物优于咪达唑仑或增强其疗效的辅助治疗，以有效治疗难治性 SE。
