title: Donepezil is a strong antagonist of voltage-gated calcium and potassium channels in molluscan neurons.
abstract: Donepezil is an acetylcholinesterase inhibitor used in Alzheimer's disease therapy. The neuroprotective effect of donepezil has been demonstrated in a number of different models of neurodegeneration including beta-amyloid toxicity. Since the mechanisms of neurodegeneration involve the activation of both Ca(2+)- and K(+)-channels, the study of donepezil action on voltage-gated ionic currents looked advisable. In the present study, the action of donepezil on voltage-gated Ca(2+)- and K(+)-channels was investigated on isolated neurons of the edible snail (Helix pomatia) using the two-microelectrodes voltage-clamp technique. Donepezil rapidly and reversibly inhibited voltage activated Ca(2+)-current (I(Ca)) (IC(50)=7.9 microM) and three types of high threshold K(+)-current: Ca(2+)-dependent K(+)-current (I(C)) (IC(50)=6.4 microM), delayed rectifier K(+)-current (I(DR)) (IC(50)=8.0 microM) and fast transient K(+)-current (I(Adepol)) (IC(50)=9.1 microM). The drug caused a dual effect on low-threshold fast transient K(+)-current (I(A)), potentiating it at low (5 microM) concentration, but inhibiting at higher (7 microM and above) concentration. Donepezil also caused a significant hyperpolarizing shift of the voltage-current relationship of I(Ca) (but not of any type of K(+)-current). Results suggest the possible contribution of the blocking effect of donepezil on the voltage-gated Ca(2+)- and K(+)-channels to the neuroprotective effect of the drug.
authors.affiliation: Brain Research Institute, Russian Academy of Medical Sciences, Per. Obukha, 5, 105064, Moscow, Russia.
authors.forename: Elena I
authors.initials: EI
authors.lastname: Solntseva
authors.forename: Julia V
authors.initials: JV
authors.lastname: Bukanova
authors.forename: Evgeny
authors.initials: E
authors.lastname: Marchenko
authors.forename: Vladimir G
authors.initials: VG
authors.lastname: Skrebitsky
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D000077265:Donepezil; D006372:Helix, Snails / Q000502:physiology; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D000077265:Donepezil