Neuroscience Graduate Program, Iowa State University, Ames, Iowa.
Epilepsy Research Laboratory, Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, Iowa.
Ann N Y Acad Sci. 2020 Nov;1479(1):75-93. doi: 10.1111/nyas.14314. Epub 2020 Feb 10.
Organophosphate (OP) nerve agents are a threat to both the military and civilians. OP exposure causes cholinergic crisis and status epilepticus (SE) because of irreversible inhibition of acetylcholinesterase that can be life-threatening if left untreated. OP survivors develop long-term morbidity, such as cognitive impairment and motor dysfunction, because of oxidative stress and progressive neuroinflammation and neurodegeneration, which act as disease promoters. Current medical countermeasures (MCMs) do not mitigate these pathologies. Therefore, our goal was to target these disease promoters using diapocynin (DPO), an NADPH oxidase inhibitor, in addition to MCMs, in a rat diisopropylfluorophosphate (DFP) model. The DFP-intoxicated rats were treated with DPO (300 mg/kg, oral, six doses, 12-h intervals) or vehicle 2 h following behavioral SE termination with diazepam. The DPO treatment significantly rescued DFP-induced motor impairment and attenuated epileptiform spiking during the first 72 h after DFP exposure in severely seizing rats despite no difference in epileptiform spike rate between the vehicle and DPO groups in mild SE rats. DPO significantly reduced DFP-induced reactive astrogliosis, neurodegeneration, GP91 , glutathiolated protein, serum nitrite, and proinflammatory cytokines and chemokines, such as interleukins (ILs) IL-1α, IL-6, IL-2, IL-17A, leptin, and IP-10, in the hippocampus. Collectively, these data support a neuroprotective role of DPO in an OP-induced neurotoxicity model.
有机磷（OP）神经毒剂对军队和平民都是一种威胁。OP 暴露会导致胆碱能危象和癫痫持续状态（SE），因为乙酰胆碱酯酶的不可逆抑制会导致生命危险，如果不治疗的话。OP 幸存者会出现长期的发病率，如认知障碍和运动功能障碍，这是由于氧化应激和进行性神经炎症和神经退行性变，这些因素作为疾病促进剂。目前的医疗对策（MCM）不能减轻这些病变。因此，我们的目标是使用 NADPH 氧化酶抑制剂地塞米松（DPO），除了 MCM 之外，还针对这些疾病促进剂，在大鼠二异丙基氟磷酸酯（DFP）模型中。DFP 中毒大鼠在行为性 SE 用地西泮终止后 2 小时，用 DPO（300mg/kg，口服，6 剂，12 小时间隔）或载体处理。尽管在轻度 SE 大鼠中，载体和 DPO 组之间的癫痫样尖峰率没有差异，但 DPO 治疗显著挽救了 DFP 诱导的运动障碍，并在 DFP 暴露后的前 72 小时内减轻了严重抽搐大鼠的癫痫样尖峰。DPO 显著减少了 DFP 诱导的反应性星形胶质细胞增生、神经退行性变、GP91 、谷胱甘肽化蛋白、血清亚硝酸盐、促炎细胞因子和趋化因子，如白细胞介素（ILs）IL-1α、IL-6、IL-2、IL-17A、瘦素和 IP-10，在海马中。总的来说，这些数据支持 DPO 在 OP 诱导的神经毒性模型中的神经保护作用。
