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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The combination of huperzine A and imidazenil is an effective strategy to prevent diisopropyl fluorophosphate toxicity in mice
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The combination of huperzine A and imidazenil is an effective strategy to prevent diisopropyl fluorophosphate toxicity in mice

机译：石杉碱甲和咪唑西尼的组合是预防二异丙基氟磷酸盐对小鼠毒性的有效策略

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摘要

Diisopropyl fluorophosphate (DFP) causes neurotoxicity related to an irreversible inhibition of acetylcholinesterase (AChE). Management of this intoxication includes: (ⅰ) pretreatment with reversible blockers of AChE, (ⅱ) blockade of muscarinic receptors with atro-pine, and (ⅲ) facilitation of GABA_A receptor signal transduction by benzodiazepines. The major disadvantage associated with this treatment combination is that it must to be repeated frequently and, in some cases, protractedly. Also, the use of diazepam (DZP) and congeners includes unwanted side effects, including sedation, amnesia, cardiorespiratory depression, and anticonvulsive tolerance. To avoid these treatment complications but safely protect against DFP-induced seizures and other CNS toxicity, we adopted the strategy of administering mice with (ⅰ) small doses of huperzine A (HUP), a reversible and long-lasting (half-life ≈5 h) inhibitor of AChE, and (ⅱ) imidazenil (IMI), a potent positive allosteric modulator of GABA action selective for as-containing GABA_A receptors. Coadministration of HUP (50 μg/kg s.c, 15 min before DFP) with IMI (2 mg/kg s.c, 30 min before DFP) prevents DFP-induced convulsions and the associated neuronal damage and mortality, allowing complete recovery within 18-24 h. In HUP-pretreated mice, the ED_(50) of IMI to block DFP-induced mortality is 10 times lower than that of DZP and is devoid of sedation. Our data show that a combination of HUP with IMI is a prophylactic, potent, and safe therapeutic strategy to overcome DFP toxicity.
机译：氟磷酸二异丙酯（DFP）引起与不可逆抑制乙酰胆碱酯酶（AChE）有关的神经毒性。这种中毒的管理包括：（ⅰ）用可逆的AChE阻断剂进行预处理，（ⅱ）用阿托品阻滞毒蕈碱受体，以及（ⅲ）苯二氮卓促进GABA_A受体信号转导。这种治疗组合的主要缺点是必须经常重复，在某些情况下需要长期重复。此外，使用地西epa（DZP）和同类药物会产生不良副作用，包括镇静，健忘，心肺抑郁和抗惊厥耐受性。为避免这些治疗并发症，但安全地防止DFP诱发的癫痫发作和其他中枢神经系统毒性，我们采取了对小鼠给予（ⅰ）小剂量石杉碱A（HUP），可逆且持久的（半衰期≈5）的策略h）AChE抑制剂，以及（I）咪哒西尼（IMI），一种有效的GABA变构作用的正变构调节剂，对含As的GABA_A受体具有选择性。 HUP（50μg/ kg sc，在DFP前15分钟）与IMI（2 mg / kg sc，在DFP前30分钟）共同给药可防止DFP诱发的惊厥及相关的神经元损伤和死亡，从而可在18-24小时内完全恢复。在HUP预处理的小鼠中，IMI的ED_（50）阻断DFP诱导的死亡率比DZP低10倍，并且没有镇静作用。我们的数据表明，HUP与IMI的组合是克服DFP毒性的预防，有效和安全的治疗策略。

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