Open AccessIn Vitro Effects of (+)MK-801 (dizocilpine) and Memantine on β-Amyloid Peptides Linked to Alzheimer’s Disease
Author(s) -
Susan E. Coombs,
Sudeep Banjade,
Ksenia Kriksunov,
Nicolina Clemente,
Jing Zhao,
Chunyu Wang,
Richard E. Gillilan,
Robert E. Oswald
Publication year - 2020
Publication title -
biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.43
H-Index - 253
eISSN - 1520-4995
pISSN - 0006-2960
DOI - 10.1021/acs.biochem.0c00813
Subject(s) - dizocilpine , memantine , nmda receptor , in vitro , chemistry , pharmacology , amyloid (mycology) , alzheimer's disease , disease , neuroscience , medicine , psychology , biochemistry , receptor , inorganic chemistry
An in vitro effect of (+)MK-801 (dizocilpine), an inhibitor of the glutamate/NMDA and nicotinic acetylcholine receptors, on the Aβ[1-42] and Aβ[1-40] peptides is described and compared to that of memantine. Memantine has been approved by the U.S. Food and Drug Administration for the treatment of mild-moderate Alzheimer's disease. Both compounds accelerated the formation of a β-sheet structure by Aβ[1-42], (+)MK-801 more rapidly than memantine, as observed in a thioflavin T fluorescence assay. The acceleration was followed by a decrease in the fluorescence signal that was not observed when the ligand was absent. Nuclear magnetic resonance spectra of the soluble peptides in the presence and absence of (+)MK-801 demonstrated that the monomeric form did not bind (+)MK-801 and that in the presence of (+)MK-801 the concentration of the monomeric form progressively decreased. Small angle X-ray scattering confirmed that the presence of (+)MK-801 resulted in a more rapid and characteristic transition to an insoluble form. These results suggest that (+)MK-801 and memantine accelerate the transition of Aβ[1-42] and Aβ[1-40] to ThT-negative insoluble forms.