Reversal of Acetylcholinesterase Inhibitor Toxicity In Vivo by Inhibitors of Choline Transport.

The antagonism of acetylcholinesterase inhibitor toxicity was studied in mice. Hemicholinium-3 (HC-3) antagonized the toxicity of physostigmine and neostigmine by shifting the dose-response curve to the right, thus increasing the LD50. However, hemicholinium-3 failed to have a protective effect against disopropylfluorophosphate (DFP), causing an enhancement of the toxicity. Hemicholinium-3 shifted the dose-response curve to the left of DFP's. Neostigmine, a quaternary nitrogen compound, increase the level of acetylcholine and choline in the brain. Since physostigmine also caused a similar response, the results indicated that neostigmine also crossed the blood-brain barrier. This was confirmed when neostigmine was shown to inhibit acetylcholinesterase following systematic administration. Pretreatment, concurrent treatment and posttreatment with hemicholinium-3 (HC-3) did not consistently decrease the effects of physostigmine and neostigmine on acetylcholine levels in either the heart or brain. Thus, hemicholinium-3 may be exerting a different effect. The protecting effect of hemicholinium-3 on acetylcholinesterase inhibitor toxicity may be due to blockage of the post-synaptic receptor at the neuromuscular junction. The discrepancy between the effect of hemicholinium-3 on the reversible and irreversible inhibitors remains unexplained.