Donepezil is a strong antagonist of voltage-gated calcium and potassium channels in molluscan neurons

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 Ca2+- 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 Ca2+- 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 Ca2+-current (ICa) (IC50 = 7.9 μM) and three types of high threshold K+-current: Ca2+-dependent K+-current (IC) (IC50 = 6.4 μM), delayed rectifier K+-current (IDR) (IC50 = 8.0 μM) and fast transient K+-current (IAdepol) (IC50 = 9.1 μM). The drug caused a dual effect on low-threshold fast transient K+-current (IA), potentiating it at low (5 μM) concentration, but inhibiting at higher (7 μM and above) concentration. Donepezil also caused a significant hyperpolarizing shift of the voltage–current relationship of ICa (but not of any type of K+-current). Results suggest the possible contribution of the blocking effect of donepezil on the voltage-gated Ca2+- and K+-channels to the neuroprotective effect of the drug.