The combination of huperzine A and imidazenil is an effective strategy to prevent diisopropyl fluorophosphate toxicity in mice

Fabio Pibiri, Alan P. Kozikowski, Graziano Pinna, James Auta, Bashkim Kadriu, Erminio Costa, Alessandro Guidotti

Research output: Contribution to journalArticle

Abstract

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 GABAA 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 α5-containing GABAA 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 ED50 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.

Original languageEnglish (US)
Pages (from-to)14169-14174
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number37
DOIs
StatePublished - Sep 16 2008

Keywords

  • GABA receptor
  • Neurotoxicity

ASJC Scopus subject areas

  • General

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