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

摘要

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 (I-Ca) (IC50=7.9 mu M) and three types of high threshold K+-current: Ca2+-dependent K+-current (I-C) (IC50=6.4 mu M), delayed rectifier K+-current (I-DR) (IC50=8.0 mu M) and fast transient K+-current (I-Adepot) (IC50=9-1 mu M). The drug caused a dual effect on low-threshold fast transient K+-current (I-A), potentiating it at low (5 mu M) concentration, but inhibiting at higher (7 mu M 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 Ca2+- and K+-channels to the neuroprotective effect of the drug. (c) 2006 Elsevier Inc. All rights reserved.