Effects of New Galantamine Derivatives in a Scopolamine Model of Dementia in Mice

Article type: Research Article

Authors: Lazarova, Maria^a | Tancheva, Lyubka^a | Alexandrova, Albena^{a; b} | Tsvetanova, Elina^a | Georgieva, Almira^a | Stefanova, Miroslava^a | Tsekova, Daniela^{c; *} | Vezenkov, Lyubomir^c | Kalfin, Reni^a | Uzunova, Diamara^a | Petkova-Kirova, Polina^{a; *}

Affiliations: [a] Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria | [b] National Sports Academy, Sofia, Bulgaria | [c] Department of Organic Chemistry, University of Chemical Technology and Metallurgy, Sofia, Bulgaria

Correspondence: [*] Correspondence to: Assoc. Prof. Polina S. Petkova-Kirova, Institute of Neurobiology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str, bl.23, Sofia 1113, Bulgaria. Tel.: +00359 898687899; E-mail: [email protected] and Dr. Daniela S. Tsekova, Department of Organic Chemistry, University of Chemical Technology and Metallurgy, Sofia, Bulgaria. E-mail: [email protected].

Abstract: Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive functions decline, is a leading cause for dementia and currently ranked as the sixth foremost cause of death. As of present, treatment of AD is symptomatic without convincing therapeutic benefits and new, effective, therapeutic agents are pursued. Due to massive loss of cholinergic neurons and decreased acetylcholine levels, cholinesterase inhibitors like galantamine, remain the backbone of pharmacological treatment of the disease. In the present study, using behavioral and biochemical methods, four newly synthesized galantamine derivatives, Gal 34, Gal 43, Gal 44, and Gal 46, were evaluated for a beneficial effect in a scopolamine model of dementia in mice. They were designed to have all the advantages of galantamine and additionally to inhibit β-secretase and exert favorable effects on plasma lipids. Behavioral tests included step-through inhibitory avoidance, T-maze, and the hole-board test, whereas biochemical evaluations involved assessment of acetylcholinesterase activity, brain monoamines levels, lipid peroxidation, catalase, glutathione peroxidase, and superoxide dismutase activities along with measurement of total glutathione. Results show that Gal 43, Gal 44, and, in particular, Gal 46 are especially effective in improving both short- and long-term memory and in the case of Gal 46 having a significant effect on exploratory activity as well. Although Gal 34 did not show behavioral effects as convincing as those of the other three galantamine derivatives, it demonstrated persuasive antioxidant and restorative capacities, making all four galantamine derivatives promising AD treatment agents and prompting further research, especially that in many of our studies they performed better than galantamine.

Keywords: Alzheimer’s disease, cholinesterase inhibitors, dementia, galantamine, scopolamine

DOI: 10.3233/JAD-215165

Journal: Journal of Alzheimer's Disease, vol. 84, no. 2, pp. 671-690, 2021