ИСТИНА

Donepezil is a potent acetylcholinesterase inhibitor used for the treatment of Alzheimer’s disease (AD). Additional therapeutically relevant target for donepezil is sigma1 receptor (Sig1-R). Beta-amyloid peptide (Aβ) is believed to contribute to the pathogenesis of AD. In our previous work (Kapai et al., 2012) we have shown that donepezil antagonizes the suppressive action of Aβ(1-42) on long-term potentiation (LTP) in rat hippocampal slices. The purpose of the present study was to determine whether Sig1-R is involved into the mechanisms of donepezil action. For this purpose, we have tested whether agonist of Sig1-R PRE-084 mimics, and antagonist of Sig1-R haloperidol abolishes the effect of donepezil. Population spikes (PS) were recorded from the pyramidal layer of the CA1 region of rat hippocampal slices. LTP of PS was induced using a train of high frequency stimulation (100 Hz, 1 s). Drugs were applied by addition to the perfusate starting15 min before and ending 5 min after the tetanus. In the control group, the amplitude of PS 30 min post-tetanus reached 153±10%. Aβ (200 nM) markedly suppressed the LTP magnitude or even caused the suppression of baseline PS (82±8%, P<0.001). This suppression of LTP could be markedly prevented when 1 µM donepezil was co-administered with Aβ (136±11%, P<0.05). Further, we co-administered three substances: Aβ, donepezil and 0.5 µM haloperidol, and have found that haloperidol antagonized the stimulating effect of donepezil on LTP (92±6%, P<0.05). Agonist of Sig1-R PRE-084 was found to reverse LTP impairment evoked by Aβ in a dose-dependent manner. The LTP amplitude 30 min post-tetanus restored to 172.4 ± 5.5% with 1 µM PRE-084 (P < 0.01). In conclusion, our observations show for the first time that selective agonist of Sig1-R PRE-084 can facilitate both control and Aβ impaired LTP, and this effect mimics the effect of donepezil. In addition to that, antagonist of Sig1-R haloperidol was found to abolish the stimulating effect of donepezil on LTP impaired by Aβ, which confirms the involvement of Sig1-R in the observed effect of donepezil.