Affiliation:
1. Institute of Neurobiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
2. Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria
Abstract
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, 3c, was evaluated in a rat model of pinealectomy (pin) followed by icvAβ1-42 infusion. Melatonin was used as the reference drug. Treatment with melatonin and 3c (10 mg/kg, i.p. for 14 days) had a beneficial effect on memory decline and the concomitant increase in hippocampal Aβ1-42 and pTAU in the pin+icvAβ1-42 rats. Melatonin supplementation facilitated non-amyloidogenic signaling via non-receptor (histone deacetylase sirtuin 1, SIRT1) and receptor-related signaling (MT/ERK/CREB). The hybrid 3c analogue up-regulated the MT1A and MT2B 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.
Funder
Bulgarian National Science Fund
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference45 articles.
1. The Amyloid Hypothesis of Alzheimer’s Disease at 25 Years;Selkoe;EMBO Mol. Med.,2016
2. Self-Reported Sleep Disturbance Is Associated with Alzheimer’s Disease Risk in Men;Benedict;Alzheimers Dement.,2015
3. Daytime Sleepiness in Mild and Moderate Alzheimer’s Disease and Its Relationship with Cognitive Impairment;Bonanni;J. Sleep Res.,2005
4. Sleep, Circadian Rhythms, and the Pathogenesis of Alzheimer Disease;Musiek;Exp. Mol. Med.,2015
5. Anderson, G., and Maes, M. (2016). Serotonin and Melatonin, CRC Press.