Pathophysiology of Anticholinesterase Agents

In this Annual and Final Report, we describe the acute, delayed, and long-term effects on rat neuromuscular junction NMJ ultrastructure and physiology following single acute injections of very low to near lethal doses of physostigmine, a reversible anticholinesterase anti-ChE compound. We describe dose-response curves for cholinesterase ChE inhibition and relate those changes to observed ultrastructural pathology and altered physiology. Using guinea pigs as alternative models to rats, we also show that the effects of sub-lethal but acute high doses of physostigmine produce similar alterations of endplate ultrastructure at similar dose levels. We describe the immediate and long-term effects on rats following 3-14 days of subacute exposures to moderate and high doses of physostigmine, and document the extent and time course of the reversibility of effects during recovery for 3-28 days following termination of subacute exposure. We compare the effects of acute physostigmine vs. pyridostigmine exposure and show that similar ultrastructural alterations are induced at similar blood ChE inhibition levels. We present physiological and ultrastructural data showing that sustained neuromuscular activity mimics many of the ultrastructural alterations produced by physostigmine and pyridostigmine, but that the alterations induced by prolonged high frequency neuromuscular activity do not result in the supercontraction of subjunctional sarcomeres that characterizes acute high-dose exposures to these potent anti-ChE agents.