Novel Brain-Penetrating Oxime Acetylcholinesterase Reactivators Attenuate Organophosphate-Induced Neuropathology in the Rat Hippocampus
Novel Brain-Penetrating Oxime Acetylcholinesterase Reactivators Attenuate Organophosphate-Induced Neuropathology in the Rat Hippocampus
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DOI：
10.1093/toxsci/kfz060
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发表时间：
2019-06-01
影响因子：
3.8
通讯作者：
Chambers, Janice E.
中科院分区：
文献类型：
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作者：
Dail, Mary B.;Leach, Charles A.;Chambers, Janice E.
有机磷（OP）抗胆碱酯酶引起过量的乙酰胆碱，导致癫痫发作，如果延长，导致啮齿动物大脑中的神经元损伤。新的取代的苯氧基烷基吡啶肟在体内试验中已经显示出穿透大鼠血脑屏障（BBB）的证据，沙林替代品（硝基苯基异丙基甲基膦酸酯，NIMP）或杀虫剂的活性代谢产物的敌百虫，对氧磷（PXN），通过减少时间停止的神经胶质细胞样行为和积累的胶质细胞酸性蛋白，而2-PAM没有。在大鼠海马中使用NeuN、Nissl和Fluoro-Jade B染色来测试我们的铅肟（15、20和55）的神经保护能力。在用NIMP或PXN进行致死水平皮下激发后，肌内给予大鼠新型肟或2-PAM加阿托品，并在第4天实施安乐死。与对照组相比，NeuN染色的NIMP、NIMP/2-PAM和NIMP/肟15组的中位损伤评分在统计学上显著增加，而NIMP/肟20和NIMP/肟55的评分与对照组无显著差异。在PXN中观察到相同的统计学显著性模式。尼氏染色提供了类似的模式，但没有统计学差异。Fluoro-Jade B表明用新型肟而不是用2-PAM对PXN的神经保护作用。与肟15相比，肟20和55的血液停留时间更长，这可能是其更大疗效的原因。这些结果表明，新肟20和55能够穿透血脑屏障和减弱神经元损伤后，NIMP和PXN暴露，表明潜在的广谱有用性。
Organophosphate (OP) anticholinesterases cause excess acetylcholine leading to seizures which, if prolonged, result in neuronal damage in the rodent brain. Novel substituted phenoxyalkyl pyridinium oximes have previously shown evidence of penetrating the rat blood-brain barrier (BBB) in in vivo tests with a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the active metabolite of the insecticide parathion, paraoxon (PXN), by reducing the time to cessation of seizure-like behaviors and accumulation of glial fibrillary acidic protein, whereas 2-PAM did not. The neuroprotective ability of our lead oximes (15, 20, and 55) was tested using NeuN, Nissl, and Fluoro-Jade B staining in the rat hippocampus. Following lethal-level subcutaneous challenge with NIMP or PXN, rats were intramuscularly administered a novel oxime or 2-PAM plus atropine and euthanized at 4 days. There were statistically significant increases in the median damage scores of the NeuN-stained NIMP, NIMP/2-PAM, and NIMP/Oxime 15 groups compared with the control whereas the scores of the NIMP/Oxime 20 and NIMP/Oxime 55 were not significantly different from the control. The same pattern of statistical significance was observed with PXN. Nissl staining provided a similar pattern, but without statistical differences. Fluoro-Jade B indicated neuroprotection from PXN with novel oximes but not with 2-PAM. The longer blood residence times of Oximes 20 and 55 compared with Oxime 15 might have contributed to their greater efficacy. These results suggest that novel oximes 20 and 55 were able to penetrate the BBB and attenuate neuronal damage after NIMP and PXN exposure, indicating potential broad-spectrum usefulness.