Redman_2022_Br.J.Pharmacol__

Reference

Title : Donepezil inhibits neuromuscular junctional acetylcholinesterase and enhances synaptic transmission and function in isolated skeletal muscle - Redman_2022_Br.J.Pharmacol__
Author(s) : Redman RR , Mackenzie H , Dissanayake KN , Eddleston M , Ribchester RR
Ref : British Journal of Pharmacology , : , 2022
Abstract :

BACKGROUND AND PURPOSE: Donepezil, a piperidine antagonist of acetylcholinesterase (AChE) prescribed for treatment of Alzheimer's Disease, has adverse neuromuscular effects in humans, including requirement for higher concentrations of non-depolarising neuromuscular blockers during surgery. Here we examined the effects of donepezil on synaptic transmission at neuromuscular junctions (NMJs) in isolated nerve-muscle preparations from mice. EXPERIMENTAL APPROACH: We measured effects of therapeutic concentrations of donepezil (10nM-1 microM) on AChE enzymic activity, muscle force responses to repetitive stimulation, and spontaneous and evoked endplate potentials (EPPs) recorded intracellularly from flexor digitorum brevis muscles. KEY RESULTS: Donepezil inhibited muscle AChE with an approximate IC50 of 30 nM. Tetanic stimulation in sub-micromolar concentrations of donepezil caused prolonged post-tetanic muscle contractions. Preliminary Fluo4-imaging indicated an association of these contractions with an increase and slow decay of intracellular Ca(2+) transients at motor endplates. Donepezil prolonged spontaneous MEPP decay time constant by about 65% and extended evoked EPP duration by a factor of almost three. The mean frequency of spontaneous MEPPs was unaffected but the incidence of "giant" MEPPs (gMEPPs), some exceeding 10 mV in amplitude, was increased. Neither mean MEPP amplitude (excluding gMEPPs), mean EPP amplitude, quantal content, or synaptic depression during repetitive stimulation were significantly altered by concentrations of donepezil up to 1 microM. CONCLUSION AND IMPLICATIONS: Adverse neuromuscular signs associated with donepezil therapy, including relative insensitivity to neuromuscular blockers, are likely due to inhibition of AChE at NMJs, prolonging the action of ACh on their postsynaptic nicotinic acetylcholine receptors but without substantively impairing evoked ACh release.

PubMedSearch : Redman_2022_Br.J.Pharmacol__
PubMedID: 36028305

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Citations formats

Redman RR, Mackenzie H, Dissanayake KN, Eddleston M, Ribchester RR (2022)
Donepezil inhibits neuromuscular junctional acetylcholinesterase and enhances synaptic transmission and function in isolated skeletal muscle
British Journal of Pharmacology :

Redman RR, Mackenzie H, Dissanayake KN, Eddleston M, Ribchester RR (2022)
British Journal of Pharmacology :