Signs of cyclosarin-induced neurotoxicity and its pharmacological treatment with quaternary pyridinium-oximes reactivators

Toxicology. 2005 Dec;216(1):32-40. doi: 10.1016/j.tox.2005.07.014. Epub 2005 Aug 26.

Abstract

Cyclosarin (GF-agent; O-cyclohexylmethylfluorophosphonate) belongs to highly toxic organophosphorus compounds. Potential for exposure to chemical warfare organophosphosphorus nerve agents, such as cyclosarin exists on the battlefield, or in the civilian sector as a threat by a terrorist group, as well as an accident as part of current demilitarization efforts. Cyclosarin was not in a front of scientific interest for long time. The research interest was increased after Operation Desert Shield and Desert Storm with the possibility (later confirmed by the UN special commission) that cyclosarin constituted the Iraqi chemical agent inventory. In this study, the neurotoxicity of cyclosarin and therapeutic efficacy of three oximes [HI-6(1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxa-propane dichloride), BI-6(2-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)-but-2-ene dibromide), HS-6(2-hydroxyiminomethylpyridinium)-3-(3-carbamoylpyridinium)-2-oxa-propane dichloride)] as acetylcholinesterase reactivators in combination with atropine was studied in rats. The therapy was administered intramusculary (i.m.) 1 min after i.m. GF-agent challenge (1 LD50). Testing of cyclosarin-induced neurotoxicity progress was carried out using the method of Functional observational battery (FOB). The experimental animals were observed at 24 h and 7 days following cyclosarin administration. The results were compared to the condition of control rats that received physiological solution instead of cyclosarin and treatment. All tested antidotal compounds induced neuroprotective efficacy, because decrease of neurotoxicity signs was recorded. There were no poisoned experimental group treated with atropine only, because our preliminary study showed no therapeutical effect of atropine alone. Cyclosarin caused a marked statistically significant change in most of the neurobehavioral parameters (FOB) at 24 h and 7 days after exposure, compared to the saline control group. Survival was 7/10 at 24 h and 5/10 at 7 days. Oxime (BI-6, HS-6 or HI-6) + atropine treatment caused a progressing recovery of the neurobehavioral disturbances caused by cyclosarin at 24 h and 7 days after exposure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidotes / administration & dosage
  • Antidotes / pharmacology
  • Antidotes / therapeutic use*
  • Behavior, Animal / drug effects
  • Chemical Warfare Agents / toxicity*
  • Injections, Intramuscular
  • Male
  • Molecular Structure
  • Neurotoxicity Syndromes / drug therapy*
  • Neurotoxicity Syndromes / etiology
  • Neurotoxicity Syndromes / physiopathology
  • Organophosphorus Compounds / toxicity*
  • Oximes
  • Pralidoxime Compounds / administration & dosage
  • Pralidoxime Compounds / pharmacology
  • Pralidoxime Compounds / therapeutic use
  • Pyridinium Compounds / administration & dosage
  • Pyridinium Compounds / pharmacology
  • Pyridinium Compounds / therapeutic use
  • Rats
  • Rats, Wistar

Substances

  • Antidotes
  • BI 6
  • Chemical Warfare Agents
  • Organophosphorus Compounds
  • Oximes
  • Pralidoxime Compounds
  • Pyridinium Compounds
  • HS 6
  • asoxime chloride
  • cyclohexyl methylphosphonofluoridate