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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 Aβ1–42 Infusion
Tchekalarova, J.; Ivanova, P.; Krushovlieva, D.; Kortenska, L.; Angelova, V.T. 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 Aβ1-42 Infusion. Int. J. Mol. Sci.2024, 25, 1867.
Tchekalarova, J.; Ivanova, P.; Krushovlieva, D.; Kortenska, L.; Angelova, V.T. 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 Aβ1-42 Infusion. Int. J. Mol. Sci. 2024, 25, 1867.
Tchekalarova, J.; Ivanova, P.; Krushovlieva, D.; Kortenska, L.; Angelova, V.T. 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 Aβ1-42 Infusion. Int. J. Mol. Sci.2024, 25, 1867.
Tchekalarova, J.; Ivanova, P.; Krushovlieva, D.; Kortenska, L.; Angelova, V.T. 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 Aβ1-42 Infusion. Int. J. Mol. Sci. 2024, 25, 1867.
Abstract
A reduction of melatonin function contributes to the acceleration of Alzheimer's disease (AD), and understanding molecular processes of melatonin-related signaling is critical for intervention of AD progression. Recently, we synthesized and tested a series of melatonin derivates with donepezil fragments in silico and in vitro. In this study, one of the most potent compounds, 3c, was studied in an in vivo rat model of pinealectomy (pin) and subsequent icvAβ1-42 infusion. Melatonin was used as a referent drug. The treatment with melatonin and 3c (10 mg/kg, i.p. for 14 days) exerted a beneficial effect on memory decline and concomitant rise of Aβ1-42 and pTAU in the hippocampus in the pin + icvAβ1-42 rats. Melatonin supplementation facilitated the non-amyloidogenic signaling via a non-receptor (histone deacetylase sirtuin 1, SIRT1) and receptor-related signaling (MT/ERK/CREB). The hybrid 3c derivate up-regulated the MT1A and MT2B receptors, pERK and pCREB. Our findings strongly support the hypothesis that melatonin-related derivates may become a promising drug candidate in AD therapy.
Biology and Life Sciences, Neuroscience and Neurology
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