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

• DOI: 10.1016/j.ejmech.2019.07.011
• Publication Date: 2019-07-05T01:59:18Z
• 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 R. Mellor; Anna Minarini
• Keywords: Amyloid-β peptide; 570; 0303 health sciences; Amyloid beta-Peptides; Coumaric Acids; Dose-Response Relationship, Drug; Molecular Structure; Cell Survival; 610; Ferulic acid; NMDA receptor; Receptors, N-Methyl-D-Aspartate; 3. Good health; Oxidative Stress; Structure-Activity Relationship; 03 medical and health sciences; Amyloid-β peptide; Ferulic acid; Memantine; NMDA receptors; Oxidative stress; Alzheimer Disease; Amyloid beta-Peptides; Cell Survival; Coumaric Acids; Dose-Response Relationship, Drug; Humans; Memantine; Molecular Structure; Neuroprotective Agents; Oxidative Stress; Receptors, N-Methyl-D-Aspartate; Structure-Activity Relationship; Tumor Cells, Cultured; Neuroprotective Agents; Alzheimer Disease; Memantine; Tumor Cells, Cultured; Oxidative stre; Humans

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.