Protective Effect of the Novel Melatonin Analogue Containing Donepezil Fragment on Memory Impairment via MT/ERK/CREB Signaling in the Hippocampus in a Rat Model of Pinealectomy and Subsequent Aβ<sub>1-42</sub> Infusion
oleh: Jana Tchekalarova, Petya Ivanova, Desislava Krushovlieva, Lidia Kortenska, Violina T. Angelova
| Format: | Article |
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| Diterbitkan: | MDPI AG 2024-02-01 |
Deskripsi
A reduction in melatonin function contributes to the acceleration of Alzheimer’s disease (AD), and understanding the molecular processes of melatonin-related signaling is critical for intervention in AD progression. Recently, we synthesized a series of melatonin analogues with donepezil fragments and tested them in silico and in vitro. In this study, one of the most potent compounds, <b>3c</b>, was evaluated in a rat model of pinealectomy (pin) followed by icvAβ<sub>1-42</sub> infusion. Melatonin was used as the reference drug. Treatment with melatonin and <b>3c</b> (10 mg/kg, i.p. for 14 days) had a beneficial effect on memory decline and the concomitant increase in hippocampal Aβ<sub>1-42</sub> and pTAU in the pin+icvAβ<sub>1-42</sub> rats. Melatonin supplementation facilitated non-amyloidogenic signaling via non-receptor (histone deacetylase sirtuin 1, SIRT1) and receptor-related signaling (MT/ERK/CREB). The hybrid <b>3c</b> analogue up-regulated the MT<sub>1A</sub> and MT<sub>2B</sub> receptors, pERK and pCREB. Our results strongly support the hypothesis that melatonin-related analogues may become a promising drug candidate for Alzheimer’s disease therapy.