Central neuroprotection demonstrated by novel oxime countermeasures to nerve agent surrogates,Annals of the New York Academy of Sciences

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Central neuroprotection demonstrated by novel oxime countermeasures to nerve agent surrogates
Annals of the New York Academy of Sciences ( IF 4.1 ) Pub Date : 2020-04-21 , DOI: 10.1111/nyas.14352
Janice E Chambers ₁ , Edward C Meek ₁

Affiliation

Oximes remain a long‐standing element of the therapy for nerve agents, organophosphates (OPs) that poison by inhibiting the enzyme acetylcholinesterase (AChE), resulting in hypercholinergic activity both centrally and peripherally. Oximes, such as the pyridinium oxime pralidoxime (2‐PAM) in the United States, can reactivate the inhibited AChE and restore cholinergic function. However, there are several drawbacks to the current oximes; one of them, the inability of these oximes to effectively enter the brain, is the subject of study by several laboratories, including ours. Our laboratory invented a platform of substituted phenoxyalkyl pyridinium oximes that were tested against highly relevant surrogates of the nerve agents, sarin and VX. Using high sublethal dosages of the OPs, the novel oximes were observed to attenuate seizure‐like behavior in rats and to reduce the levels of glial fibrillary acidic protein (an indicator of glial scarring) to control levels, in contrast to levels observed with 2‐PAM or no oxime therapy. Using lethal levels of surrogates, some novel oximes protected against lethality compared with 2‐PAM, shortened the time to cessation of seizure‐like behavior (from 8+ to 6 h), and protected the brain neurons. Therefore, some of these novel oximes are showing exceptional promise alone or in combination with 2‐PAM as therapeutics against nerve agent toxicity.

中文翻译：

神经毒剂替代物的新型肟对策证明了中枢神经保护作用

肟仍然是神经毒剂、有机磷酸盐 (OPs) 治疗的长期元素，它通过抑制乙酰胆碱酯酶 (AChE) 中毒，导致中枢和外周的高胆碱能活性。肟类药物，如美国的吡啶肟解磷定（2-PAM），可以重新激活被抑制的 AChE 并恢复胆碱能功能。然而，目前的肟有几个缺点；其中之一，这些肟不能有效地进入大脑，是包括我们在内的几个实验室研究的主题。我们的实验室发明了一个取代苯氧基烷基吡啶肟的平台，该平台针对神经毒剂沙林和 VX 的高度相关替代物进行了测试。使用高亚致死剂量的 OP，与使用 2-PAM 或无肟治疗观察到的水平相比，观察到新的肟可减轻大鼠的癫痫样行为，并降低胶质纤维酸性蛋白（胶质瘢痕形成的指标）的水平以控制水平。使用致死水平的替代物，与 2-PAM 相比，一些新的肟可防止致死性，缩短癫痫样行为停止的时间（从 8 小时以上至 6 小时），并保护脑神经元。因此，这些新型肟中的一些单独或与 2-PAM 组合作为神经毒剂毒性的治疗剂显示出非凡的前景。与 2-PAM 相比，一些新的肟可防止致死性，缩短癫痫样行为停止的时间（从 8+ 到 6 小时），并保护脑神经元。因此，这些新型肟中的一些单独或与 2-PAM 组合作为神经毒剂毒性的治疗剂显示出非凡的前景。与 2-PAM 相比，一些新的肟可防止致死性，缩短癫痫样行为停止的时间（从 8+ 到 6 小时），并保护脑神经元。因此，这些新型肟中的一些单独或与 2-PAM 组合作为神经毒剂毒性的治疗剂显示出非凡的前景。

更新日期：2020-04-21

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