Donepezil in low micromolar concentrations modulates voltage-gated potassium currents in pyramidal neurons of rat hippocampus

Donepezil is a cholinesterase inhibitor widely used for the treatment of Alzheimer's disease. Voltage-gated K+-channels are discussed as possible targets for the drug, but the results obtained by different authors are contradictory. In the present study performed on pyramidal cells isolated from rat's hippocampus, we investigated the effect of donepezil on delayed rectifier K+-current (I-K(DR)) and transient outward K+-current (I-K(A)) using patch-clamp technique. The inhibitory effect of donepezil on I-K(DR) was found in all the cells tested, but its strength varied in different cells. Two groups of neurons were differing in their sensitivity to donepezil: more sensitive (IC50 = 8.9 mu M) and less sensitive (IC50 = 114.9 mu M). The effect of the drug on I-K(DR) was rapid, reversible and voltage-dependent, increasing with depolarization. Donepezil modulated I-K(A) in two different ways: in some cells it suppressed the current with the IC50 value of 23.4 mu M, while in other cells it augmented the current with a bell-shaped dose-response curve. Maximal (about twofold) enhancement of I-K(A) amplitude was caused by 10 mu M donepezil. Augmentation of I-K(A) increased with membrane depolarization. Our results show for the first time that voltage-dependent potassium channels in mammals' neurons are effectively modulated by low micromolar concentrations of donepezil. (C) 2012 Elsevier Inc. All rights reserved.