The involvement of the NMDA receptor complex in the protective effect of anticholinergic drugs against soman poisoning.

Abstract

Organophosphate poisoning is associated with adverse effects on the central nervous system such as seizure/convulsive activity and long term changes in neuronal networks. This study reports on investigations designed to assess the consequences of soman exposure on excitatory amino acids receptors in the rat brain. In addition, the protective effects of caramiphen which acts at these receptors, and scopolamine, which does not, was determined on soman-induced alteration in rat brain functions. Administration of soman (1xLD50) to pyridostigmine pretreated rats produced seizure activity (measured by EEG monitoring) in all animals tested. Estimation of [3H]MK-801 binding to brain membranes from intoxicated rats revealed a marked decrease in Bmax value 24 but not 2 hrs following soman administration. The specific nature of these effects of soman was demonstrated by the findings that [3H]flunitrazepam binding to central benzodiazepine receptors remained unchanged in soman-poisoned rat brain membranes. Both scopolamine and caramiphen, when used prophylactically prevented the lethal effect of soman and completely blocked the development of electrographic seizure activity (EGSA). In contrast, only caramiphen abolished soman-induced modifications in NMDA/ion channel characteristics. Caramiphen displaced [3H]MK-801 bound to the NMDA/ion channel complex, possibly by interacting with the Zn2+ site whereas scopolamine did not. Moreover, caramiphen, but not scopolamine, partially protected mice from NMDA-induced lethality. Thus, it is suggested that an important component of the protective efficacy of caramiphen against organophosphate poisoning might be attributed to its ability to modulate NMDA receptors in addition to its anticholinergic properties.

• Authors: L Raveh, S Chapman, G Cohen, D Alkalay, E Gilat, I Rabinovitz, B A Weissman
• Journal: Neurotoxicology (Neurotoxicology) Vol. 20 Issue 4 Pg. 551-9 (Aug 1999) ISSN: 0161-813X [Print] Netherlands
• PMID: 10499354 (Publication Type: Journal Article)

Chemical References

• Cholinesterase Inhibitors
• Cyclopentanes
• Excitatory Amino Acid Antagonists
• Parasympatholytics
• Receptors, GABA-A
• Receptors, Glutamate
• Receptors, N-Methyl-D-Aspartate
• Flunitrazepam
• Dizocilpine Maleate
• Soman
• caramiphen
• Scopolamine
• Pyridostigmine Bromide

Topics

• Animals
• Brain (drug effects, metabolism)
• Cholinesterase Inhibitors (toxicity)
• Cyclopentanes (pharmacology)
• Dizocilpine Maleate (metabolism)
• Dose-Response Relationship, Drug
• Drug Interactions
• Electroencephalography (drug effects)
• Excitatory Amino Acid Antagonists (pharmacology)
• Flunitrazepam (metabolism)
• In Vitro Techniques
• Male
• Mice
• Mice, Inbred ICR
• Parasympatholytics (pharmacology)
• Protein Binding
• Pyridostigmine Bromide (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, GABA-A (metabolism)
• Receptors, Glutamate (drug effects)
• Receptors, N-Methyl-D-Aspartate (physiology)
• Scopolamine (pharmacology)
• Seizures (chemically induced)
• Soman (toxicity)
• Time Factors