Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, United States.
Department of Medicine, National Jewish Health, Denver, CO, United States.
Redox Biol. 2019 Jan;20:275-284. doi: 10.1016/j.redox.2018.10.010. Epub 2018 Oct 16.
Persistent inhibition of acetylcholinesterase resulting from exposure to nerve agents such as soman, is associated with prolonged seizure activity known as status epilepticus (SE). Without medical countermeasures, exposure to soman and resultant SE leads to high morbidity and mortality. Currently available therapeutics are effective in limiting mortality, however effects on morbidity are highly time-dependent and rely on the ability to suppress SE. We have previously demonstrated significant protection from secondary neuronal injury in surrogate nerve agent models by targeting oxidative stress. However, whether oxidative stress represents a relevant therapeutic target in genuine nerve agent toxicity is unknown. Here, we demonstrate that soman exposure results in robust region- and time-dependent oxidative stress. Targeting this oxidative stress in a post-exposure paradigm using a small molecular weight, broad spectrum catalytic antioxidant, was sufficient to attenuate brain and plasma oxidative stress, neuroinflammation and neurodegeneration. Thus, targeting of oxidative stress in a post-exposure paradigm can mitigate secondary neuronal injury following soman exposure.
持续抑制乙酰胆碱酯酶，导致接触到神经毒剂，如沙林，与长时间的癫痫发作活动，称为癫痫持续状态（SE）有关。如果没有医疗对策，接触沙林和由此产生的 SE 会导致高发病率和死亡率。目前可用的疗法在限制死亡率方面是有效的，然而，对发病率的影响高度依赖于抑制 SE 的能力，而且具有很强的时间依赖性。我们之前已经在替代神经毒剂模型中通过靶向氧化应激，证明了对继发性神经元损伤有显著的保护作用。然而，氧化应激是否代表真正的神经毒剂毒性的一个相关治疗靶点尚不清楚。在这里，我们证明了沙林暴露会导致强烈的区域和时间依赖性氧化应激。在暴露后的模型中使用一种小分子、广谱催化抗氧化剂来靶向这种氧化应激，足以减轻大脑和血浆中的氧化应激、神经炎症和神经退行性变。因此，在暴露后的模型中靶向氧化应激可以减轻沙林暴露后的继发性神经元损伤。
