title: The combination of huperzine A and imidazenil is an effective strategy to prevent diisopropyl fluorophosphate toxicity in mice.
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 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 approximately 5 h) inhibitor of AChE, and (ii) imidazenil (IMI), a potent positive allosteric modulator of GABA action selective for alpha(5)-containing GABA(A) receptors. Coadministration of HUP (50 microg/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 approximately 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.
authors.affiliation: Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, Chicago, IL 60612, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Pibiri
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Graziano
authors.initials: G
authors.lastname: Pinna
authors.forename: James
authors.initials: J
authors.lastname: Auta
authors.forename: Bashkim
authors.initials: B
authors.lastname: Kadriu
authors.forename: Erminio
authors.initials: E
authors.lastname: Costa
authors.forename: Alessandro
authors.initials: A
authors.lastname: Guidotti
mesh_terms: D000470:Alkaloids; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000517:prevention & control; D004359:Drug Therapy, Combination; D007093:Imidazoles / Q000494:pharmacology*; D007531:Isoflurophate / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D007928:Lethal Dose 50; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D007093:Imidazoles; D012717:Sesquiterpenes; C050426:huperzine A; D001569:Benzodiazepines; D007531:Isoflurophate; C082661:imidazenil
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