Abstract
Alzheimer’s disease (AD) is a worldwide problem, and there are currently no treatments that can stop this disease. To investigate the binding affinity of 6-((4-fluorophenyl) selanyl)-9H-purine (FSP) with acetylcholinesterase (AChE), to verify the effects of FSP in an AD model in mice and to evaluate the toxicological potential of this compound in mice. The binding affinity of FSP with AChE was investigated by molecular docking analyses. The AD model was induced by streptozotocin (STZ) in Swiss mice after FSP treatment (1 mg/kg, intragastrically (i.g.)), 1st-10th day of the experimental protocol. Anxiety was evaluated in an elevated plus maze test, and memory impairment was evaluated in the Y-maze, object recognition and step-down inhibitory avoidance tasks. The cholinergic system was investigated based on by looking at expression and activity of AChE and expression of choline acetyltransferase (ChAT). We evaluated expression and activity of Na+/K+-ATPase. For toxicological analysis, animals received FSP (300 mg/kg, i.g.) and aspartate aminotransferase, alanine aminotransferase activities were determined in plasma and δ-aminolevulinate dehydratase activity in brain and liver. FSP interacts with residues of the AChE active site. FSP mitigated the induction of anxiety and memory impairment caused by STZ. FSP protected cholinergic system dysfunction and reduction of activity and expression of Na+/K+-ATPase. FSP did not modify toxicological parameters evaluated and did not cause the death of mice. FSP protected against anxiety, learning and memory impairment with involvement of the cholinergic system and Na+/K+-ATPase in these actions.
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The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Acknowledgments
We are grateful for the financial support and scholarships from the Brazilian agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (UNIVERSAL 408874/2016-3 and 429859/2018-0), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) (PRONEM 16/2551-0000240-1, PRONUPEQ 16/2551-0000526-5 and PqG 17/2551-0001013-2 and 19/2551-0001745-6). CNPq is also acknowledged for the fellowships granted to C.L., D.A. and E.A.W., L.S., V.F.C. This study was funded in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível superior – Brasil (CAPES) - Finance Code 001.
Funding
This study received financial support and scholarships from the following Brazilian agencies: CNPq (UNIVERSAL 408874/2016–3 and 429859/2018–0), FAPERGS (PRONEM 16/2551–0000240-1, PRONUPEQ 16/2551–0000526-5 and PqG 17/2551–0001013-2 and 19/2551–0001745-6). CNPq is also acknowledged for the fellowships granted to C.L., D.A. and E.A.W., L.S., V.F.C. This study was also financed in part by the CAPES- Finance Code 001.
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MPP: Conceptualization, Methodology, Formal analysis, Investigation, Writing - Original Draft. CL and EAW: Conceptualization, Verification, Resources, Writing - Review & Editing, Supervision, Project administration, Funding acquisition. LS, DA and VFC: Methodology, Formal analysis, Funding acquisition. AGV, KCR, ASR, EBB and LFBD: Methodology. MGF: Methodology, Formal analysis, Writing Original Draft. WBD: Methodology, Formal analysis.
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Pinz, M.P., Vogt, A.G., da Costa Rodrigues, K. et al. Effect of a purine derivative containing selenium to improve memory decline and anxiety through modulation of the cholinergic system and Na+/K+-ATPase in an Alzheimer’s disease model. Metab Brain Dis 36, 871–888 (2021). https://doi.org/10.1007/s11011-021-00703-w
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DOI: https://doi.org/10.1007/s11011-021-00703-w