Objective: The antidementia drug donepezil, is widely used for the treatment of Alzheimer’s disease (AD). The mechanism of therapeutic action of donepezil is believed to be conditioned by the enhancement of cholinergic neurotransmission in AD patients through the inhibition of acetylcholinesterase (Sugimoto, 2000). In this study, we examined another possible target for donepezil, that is voltage-gated ionic channels of neuronal membrane.
Design: The experiments were performed on isolated neurons of the land snail. A tablet of Aricept (Pfizer) containing 5 mg donepezil hydrochloride was dissolved in the extracellular solution and introduced into the bath medium. The final concentration of donepezil was 5 or 10 microM. The duration of cell exposure to a drug was 10 min, and washing time was 20-30 min.
Materials and Methods: Two-microelectrode voltage clamp method was used to measure the voltage-gated potassium (I.K) and voltage-gated calcium (I.Ca) currents.
Results: It was found that both I.K and I.Ca of molluscan neurons were rapidly and reversibly inhibited by donepezil in all cells tested (n=14). The effect appeared 1-2 min after drug application, reached a maximum in 2-5 min, and was washed out in 10-20 min. The I.K was appeared to be more sensitive to donepezil than I.Ca. The maximal amplitude of I.Ca was decreased by 10% and 42% on average with 5 and 10 microM donepezil, accordingly. The peak amplitude of total I.K recorded at +30 mV was inhibited more strongly with donepezil: by 35% and 90% on average in the presence of 5 and 10 microM of a drug, accordingly. To divide the total I.K into slow-inactivating and fast-inactivating components, two selective antagonists of potassium channels were used: tetraethylammonium (TEA, 5 mM) and 4-aminopyridine (4-AP, 5mM). It was found that 5 microM donepezil effectively inhibited TEA-sensitive slow-inactivating potassium current, but did not affect the transient 4-AP-sensitive potassium current (I.A).
Conclusion: The results of present study are in line with our previous findings that nootropic drugs, vinpocetine and piracetam, selectively block TEA-sensitive potassium current (Bukanova et al., 2002). It is also worth to note that beta-amyloid, a peptide that is widely believed to play a critical role in the pathophysiology of AD, increases TEA-sensitive potassium current (Colom et al., 1998; Yu et al., 1998).
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