Masson Patrick, Nachon Florian
Neuropharmacology Laboratory, Kazan Federal University, Kazan, Russia.
Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, Cédex, France.
J Neurochem. 2017 Aug;142 Suppl 2:26-40. doi: 10.1111/jnc.14026. Epub 2017 May 21.
Organophosphorus agents (OPs) irreversibly inhibit acetylcholinesterase (AChE) causing a major cholinergic syndrome. The medical counter-measures of OP poisoning have not evolved for the last 30 years with carbamates for pretreatment, pyridinium oximes-based AChE reactivators, antimuscarinic drugs and neuroprotective benzodiazepines for post-exposure treatment. These drugs ensure protection of peripheral nervous system and mitigate acute effects of OP lethal doses. However, they have significant limitations. Pyridostigmine and oximes do not protect/reactivate central AChE. Oximes poorly reactivate AChE inhibited by phosphoramidates. In addition, current neuroprotectants do not protect the central nervous system shortly after the onset of seizures when brain damage becomes irreversible. New therapeutic approaches for pre- and post-exposure treatments involve detoxification of OP molecules before they reach their molecular targets by administrating catalytic bioscavengers, among them phosphotriesterases are the most promising. Novel generation of broad spectrum reactivators are designed for crossing the blood-brain barrier and reactivate central AChE. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.
有机磷制剂（OPs）会不可逆地抑制乙酰胆碱酯酶（AChE），引发严重的胆碱能综合征。在过去30年里，OP中毒的医学应对措施并未改进，仍采用氨基甲酸盐进行预处理，基于吡啶肟的AChE复活剂、抗毒蕈碱药物以及神经保护性苯二氮䓬类药物进行暴露后治疗。这些药物可确保对周围神经系统的保护，并减轻OP致死剂量的急性影响。然而，它们存在显著局限性。吡啶斯的明和肟类药物无法保护/复活中枢AChE。肟类药物对被磷酰胺酯抑制的AChE的复活效果不佳。此外，当脑损伤变得不可逆时，目前的神经保护剂在癫痫发作后不久无法保护中枢神经系统。暴露前和暴露后治疗的新方法包括通过施用催化性生物清除剂在OP分子到达其分子靶点之前对其进行解毒，其中磷酸三酯酶最具前景。新一代广谱复活剂旨在穿越血脑屏障并复活中枢AChE。本文是为第十五届国际胆碱能机制研讨会特刊撰写的文章。
