Tailored Melatonin- and Donepezil-Based Hybrids Targeting Pathognomonic Changes in Alzheimer’s Disease: An In Vitro and In Vivo Investigation

Author:

Mihaylova Rositsa1ORCID,Angelova Violina T.1ORCID,Tchekalarova Jana2ORCID,Atanasova Dimitrinka23ORCID,Ivanova Petja2,Simeonova Rumyana1ORCID

Affiliation:

1. Department “Pharmacology, Pharmacotherapy and Toxicology”, Faculty of Pharmacy, Medical University of Sofia, 1431 Sofia, Bulgaria

2. Institute of Neurobiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria

3. Department of Anatomy, Faculty of Medicine, Trakia University, 6003 Stara Zagora, Bulgaria

Abstract

A plethora of pathophysiological events have been shown to play a synergistic role in neurodegeneration, revealing multiple potential targets for the pharmacological modulation of Alzheimer’s disease (AD). In continuation to our previous work on new indole- and/or donepezil-based hybrids as neuroprotective agents, the present study reports on the beneficial effects of lead compounds of the series on key pathognomonic features of AD in both cellular and in vivo models. An enzyme-linked immunosorbent assay (ELISA) was used to evaluate the anti-fibrillogenic properties of 15 selected derivatives and identify quantitative changes in the formation of neurotoxic β-amyloid (Aβ42) species in human neuronal cells in response to treatment. Among the most promising compounds were 3a and 3c, which have recently shown excellent antioxidant and anticholinesterase activities, and, therefore, have been subjected to further in vivo investigation in mice. An acute toxicity study was performed after intraperitoneal (i.p.) administration of both compounds, and 1/10 of the LD50 (35 mg/kg) was selected for subacute treatment (14 days) with scopolamine in mice. Donepezil (DNPZ) and/or galantamine (GAL) were used as reference drugs, aiming to establish any pharmacological superiority of the multifaceted approach in battling hallmark features of neurodegeneration. Our promising results give first insights into emerging disease-modifying strategies to combine multiple synergistic activities in a single molecule.

Funder

Bulgarian National Science Fund

Publisher

MDPI AG

Reference58 articles.

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