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Merging memantine and ferulic acid to probe connections between NMDA receptors, oxidative stress and amyloid-β peptide in Alzheimer's disease

Rosini, Michela; Simoni, Elena; Caporaso, Roberta; Basagni, Filippo; Catanzaro, Michele; Abu, Izuddin F.; Fagiani, Francesca; Fusco, Federica; Masuzzo, Sara; Albani, Diego; Lanni, Cristina; Mellor, Ian R.; Minarini, Anna

Authors

Michela Rosini

Elena Simoni

Roberta Caporaso

Filippo Basagni

Michele Catanzaro

Izuddin F. Abu

Francesca Fagiani

Federica Fusco

Sara Masuzzo

Diego Albani

Cristina Lanni

IAN MELLOR ian.mellor@nottingham.ac.uk
Assistant Professor

Anna Minarini



Abstract

N-methyl-d-aspartate receptors (NMDAR) are critically involved in the pathogenesis of Alzheimer's disease (AD). Acting as an open-channel blocker, the anti-AD drug memantine preferentially targets NMDAR overactivation, which has been proposed to trigger neurotoxic events mediated by amyloid β peptide (Aβ) and oxidative stress. In this study, we applied a multifunctional approach by conjugating memantine to ferulic acid, which is known to protect the brain from Aβ neurotoxicity and neuronal death caused by ROS. The most interesting compound (7) behaved, like memantine, as a voltage-dependent antagonist of NMDAR (IC50 = 6.9 μM). In addition, at 10 μM concentration, 7 exerted antioxidant properties both directly and indirectly through the activation of the Nrf-2 pathway in SH-SY5Y cells. At the same concentration, differently from the parent compounds memantine and ferulic acid alone, it was able to modulate Aβ production, as revealed by the observed increase of the non-amyloidogenic sAPPα in H4-SW cells. These findings suggest that compound 7 may represent a promising tool for investigating NMDAR-mediated neurotoxic events involving Aβ burden and oxidative damage.

Citation

Rosini, M., Simoni, E., Caporaso, R., Basagni, F., Catanzaro, M., Abu, I. F., …Minarini, A. (2019). Merging memantine and ferulic acid to probe connections between NMDA receptors, oxidative stress and amyloid-β peptide in Alzheimer's disease. European Journal of Medicinal Chemistry, 180, 111-120. https://doi.org/10.1016/j.ejmech.2019.07.011

Journal Article Type Article
Acceptance Date Jul 3, 2019
Online Publication Date Jul 5, 2019
Publication Date Oct 15, 2019
Deposit Date Sep 4, 2019
Publicly Available Date Jul 6, 2020
Journal European Journal of Medicinal Chemistry
Print ISSN 0223-5234
Electronic ISSN 1768-3254
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 180
Pages 111-120
DOI https://doi.org/10.1016/j.ejmech.2019.07.011
Keywords Organic Chemistry; Pharmacology; Drug Discovery; General Medicine
Public URL https://nottingham-repository.worktribe.com/output/2563325
Publisher URL https://www.sciencedirect.com/science/article/pii/S0223523419306324?via%3Dihub
Additional Information This article is maintained by: Elsevier; Article Title: Merging memantine and ferulic acid to probe connections between NMDA receptors, oxidative stress and amyloid-β peptide in Alzheimer's disease; Journal Title: European Journal of Medicinal Chemistry; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.ejmech.2019.07.011; Content Type: article; Copyright: © 2019 Elsevier Masson SAS. All rights reserved.

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