Donepezil inhibits neuromuscular junctional acetylcholinesterase and enhances synaptic transmission and function in isolated skeletal muscle.

Autor: Redman RR; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK., Mackenzie H; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK., Dissanayake KN; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK., Eddleston M; Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK., Ribchester RR; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2022 Dec; Vol. 179 (24), pp. 5273-5289. Date of Electronic Publication: 2022 Sep 15.
DOI: 10.1111/bph.15940
Abstrakt: Background and Purpose: Donepezil, a piperidine inhibitor 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 (10 nM to 1 μM) on AChE enzymic activity, muscle force responses to repetitive stimulation, and spontaneous and evoked endplate potentials (EPPs) recorded intracellularly from flexor digitorum brevis muscles from CD01 or C57BlWld S mice.
Key Results: Donepezil inhibited muscle AChE with an approximate IC 50 of 30 nM. Tetanic stimulation in sub-micromolar concentrations of donepezil 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 miniature EPP (MEPP) decay time constants by about 65% and extended evoked EPP duration almost threefold. 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 μM.
Conclusion and Implications: Adverse neuromuscular signs associated with donepezil therapy, including relative insensitivity to neuromuscular blockers, are probably due to inhibition of AChE at NMJs, prolonging the action of ACh on postsynaptic nicotinic acetylcholine receptors but without substantively impairing evoked ACh release.
(© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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