Donepezil in a Narrow Concentration Range Augments Control and Impaired by Beta-Amyloid Peptide Hippocampal LTP in NMDAR-Independent Manner

Acetylcholinesterase (AChE) inhibitor donepezil is widely used for the treatment of Alzheimer's disease (AD). The mechanisms of therapeutic effects of the drug are not well understood. The ability of donepezil to reverse a known pathogenic effect of beta-amyloid peptide (Abeta), namely, the impairment of hippocampal long-term potentiation (LTP), was not studied yet. The goal of the present study was to study the influence of donepezil in 0.1-10 mu M concentrations on control and Abeta-impaired hippocampal LTP. Possible involvement of N-methyl-D-aspartate receptors (NMDARs) into mechanisms of donepezil action was also studied. LTP of population spike (PS) was studied in the CA1 region of rat hippocampal slices. Change of LTP by donepezil treatment had a bell-shaped dose-response curve. The drug in concentrations of 0.1 and 1 mu M did not change LTP while in concentration of 0.5 mu M significantly increased it, and in concentration of 5 and 10 mu M suppressed LTP partially or completely. Abeta (200 nM) markedly suppressed LTP. Addition of 0.1, 0.5 or 1 mu M donepezil to Abeta solution caused a restoration of LTP. N-methyl-D-aspartate (NMDA) currents were studied in acutely isolated pyramidal neurons from CA1 region of rat hippocampus. Neither Abeta, nor 0.5 mu M donepezil were found to change NMDA currents, while 10 mu M donepezil rapidly and reversibly depressed it. Results suggest that donepezil augments control and impaired by Abeta hippocampal LTP in NMDAR-independent manner. In general, our findings extend the understanding of mechanisms of therapeutic action of donepezil, especially at an early stage of AD, and maybe taken into account while considering the possibility of donepezil overdose.