Organophosphate Cholinesterase Inhibitor (Diisopropylfluorophosphate) Induces Acetylcholinesterase-mediated Nicotinic Receptor Facilitation

J Korean Neurol Assoc > Volume 18(6); 2000 > Article

Journal of the Korean Neurological Association 2000;18(6): 735-740.

유기인산염 아세틸콜린에스터레이스 억제제 (Diisopropylfluorophosphate)가 니코틴성 아세틸콜린 수용체의 기능에 미치는 효과

성정준, ·박경석 ·이광우

서울대학교 의과대학 신경과학교실

Organophosphate Cholinesterase Inhibitor (Diisopropylfluorophosphate) Induces Acetylcholinesterase-mediated Nicotinic Receptor Facilitation

Jung-Joon Sung, M.D., Kyung-Seok Park, M.D., Kwang-Woo Lee, M.D.

Department of Neurology, College of Medicine, Seoul National University, Seoul, Korea

Abstract

Background: Cholinesterase inhibitors (ChEIs) which have been widely used clinically are known to have diverse actions on the neuromuscular synaptic transmissions, suggesting that inhibiting cholinesterase (ChE) might not be their only mode of action. ChEIs interact with the nicotinic acetylcholine receptor (nAChR) macromolecule as a weak ago-nist, and as a modulator inducing desensitization and blockade at high concentrations. In a previous study, we reported that carbamate ChEIs, Pyridostigmine and Physostigmine could facilitate the ionic influx through nAChRs, when pre-cluding the Ach-hydrolyzing effect of acetylChE (AChE) by applying carbachol as an agonist. The facilitation of the nAChR function was supposed to be achieved by AChE-mediated nAChR modulation and possibly by the up-regulation of nAChRs. Methods : In this study, we analyzed the effect of irreversible organophosphate ChEI, diisopropylfluo-rophosphate (DFP) on the function of muscular nAChRs in TE671 cells, quantifying carbachol-induced intracellular 22 Na+ influx through nAChRs, using radioassay. Results : Preincubation of cells with 1 mM DFP at 37 ℃for 10 min as well as the simultaneous application of carbachol and DFP, decreased the carbachol-induced influx dose-dependently.However, preincubation of cells with 10 μM DFP potentiated the influx to 132.5±7.4% CPM. Moreover, Najar Tx com-pletely inhibited the potentiated 22 Na + influx. Conclusions : Organophosphate ChEI can facilitate nAChR functions at low concentrations with a yet discovered mechanism, which is supposed to necessitate cellular metabolism, and be pos-sibly mediated by AChE. The inhibition of DFP on nAChR functions at high concentration is attributable to its remained curare-like actions and direct cellular toxicity.J Korean Neurol Assoc 18(6):735~740, 2000Key Words : Diisopropylfluorophosphate (DFP), Organophosphate cholinesterase inhibitor,