The combination of huperzine A and imidazenil is an effective strategy to prevent diisopropyl fluorophosphate toxicity in mice.
The combination of huperzine A and imidazenil is an effective strategy to prevent diisopropyl fluorophosphate toxicity in mice.
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石杉碱甲和咪达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。
DOI：
10.1073/pnas.0807172105
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发表时间：
2008
影响因子：
11.1
通讯作者：
Guidotti,Alessandro
中科院分区：
文献类型：
--
作者：
Pibiri,Fabio;Kozikowski,AlanP;Pinna,Graziano;Auta,James;Kadriu,Bashkim;Costa,Erminio;Guidotti,Alessandro
氟磷酸二异丙酯(DFP)引起的神经毒性与乙酰胆碱酯酶(AChE)的不可逆抑制有关。对这种中毒的处理包括：(I)用可逆性AChE阻滞剂预处理，(Ii)用阿托品阻断M受体，(Iii)苯二氮卓类药物促进GABAA受体的信号转导。与这种治疗组合相关的主要缺点是必须频繁重复，在某些情况下，还需要长期重复。此外，安定(DZP)及其类似物的使用包括不良副作用，包括镇静、健忘、心肺抑制和抗惊厥耐受性。为了避免这些治疗并发症，同时安全地预防DFP诱导的癫痫发作和其他中枢神经系统毒性，我们采用了以下策略：(I)小剂量石杉碱甲(HUP)，一种可逆的长期(半衰期≈为5h)的AChE抑制剂；(Ii)咪达西尼，一种有效的正性变构调节剂，选择性地作用于含有α5的GABA受体。HUP(50μg/kg S.C.，DFP前15分钟)与IMI(2 mg/kg S.C.，DFP前30分钟)联用可防止DFP诱发的惊厥及相关的神经元损伤和死亡，可在18-24小时内完全恢复。在HUP预处理的小鼠中，IMI阻断DFP诱导的死亡的ED50比DZP低10倍，且没有镇静作用。我们的数据表明，HUP和IMI的结合是一种预防、有效和安全的治疗策略，可以克服DFP的毒性。
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 atropine, and (iii) facilitation of GABAAreceptor 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 α5-containing GABAAreceptors. 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 ED50of 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.