Affiliations 

  • 1 Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. Electronic address: michela.rosini@unibo.it
  • 2 Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy
  • 3 Department of Drug Sciences (Pharmacology Section), University of Pavia, V.le Taramelli 14, 27100, Pavia, Italy
  • 4 School of Life Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK; Universiti Kuala Lumpur, Institute of Medical Science Technology, A1-1, Jalan TKS1, Taman Kajang Sentral, 43000, Kajang, Selangor, Malaysia
  • 5 Department of Drug Sciences (Pharmacology Section), University of Pavia, V.le Taramelli 14, 27100, Pavia, Italy; Scuola Universitaria Superiore IUSS Pavia, P.zza Vittoria, 15, 27100, Pavia, Italy
  • 6 Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy
  • 7 School of Life Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
  • 8 Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. Electronic address: anna.minarini@unibo.it
Eur J Med Chem, 2019 Oct 15;180:111-120.
PMID: 31301562 DOI: 10.1016/j.ejmech.2019.07.011

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.