title: NMDA antagonists exert distinct effects in experimental organophosphate or carbamate poisoning in mice.
abstract: Organophosphate (OP) and carbamate acetylcholinesterase (AChE) inhibitors produce seizures and lethality in mammals. Anticonvulsant and neuroprotective properties of N-methyl-D-aspartate (NMDA) antagonists encourage the investigation of their effects in AChE inhibitor-induced poisonings. In the present study, the effects of dizocilpine (MK-801, 1 mg/kg) or 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 10 mg/kg), alone or combined with muscarinic antagonist atropine (1.8 mg/kg), on convulsant and lethal properties of an OP pesticide dichlorvos or a carbamate drug physostigmine, were studied in mice. Both dichlorvos and physostigmine induced dose-dependent seizure activity and lethality. Atropine did not prevent the occurrence of convulsions but decreased the lethal effects of both dichlorvos and physostigmine. MK-801 or CPP blocked or attenuated, respectively, dichlorvos-induced convulsions. Contrariwise, NMDA antagonists had no effect in physostigmine-induced seizures or lethality produced by dichlorvos or physostigmine. Concurrent pretreatment with atropine and either MK-801 or CPP blocked or alleviated seizures produced by dichlorvos, but not by physostigmine. Both MK-801 and CPP co-administered with atropine enhanced its antilethal effects in both dichlorvos and physostigmine poisoning. In both saline- and AChE inhibitor-treated mice, no interaction of the investigated antidotes with brain cholinesterase was found. The data indicate that both muscarinic ACh and NMDA receptor-mediated mechanisms contribute to the acute toxicity of AChE inhibitors, and NMDA receptors seem critical to OP-induced seizures.
authors.affiliation: Department of Toxicology, Institute of Agricultural Medicine, 20-090 Lublin, Poland. andrzej.dekundy@merz.de <andrzej.dekundy@merz.de>
authors.forename: Andrzej
authors.initials: A
authors.lastname: Dekundy
authors.forename: Rafal M
authors.initials: RM
authors.lastname: Kaminski
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Zielinska
authors.forename: Waldemar A
authors.initials: WA
authors.lastname: Turski
mesh_terms: D000818:Animals; D001285:Atropine / Q000627:therapeutic use; D002219:Carbamates / Q000506:poisoning*; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D004006:Dichlorvos / Q000506:poisoning*; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*
chemical_list: D002219:Carbamates; D002800:Cholinesterase Inhibitors; D010879:Piperazines; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D001285:Atropine; D004006:Dichlorvos; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid