posted on 2020-08-11, 18:50authored byF. Javier Pérez-Areales, María Garrido, Ester Aso, Manuela Bartolini, Angela De Simone, Alba Espargaró, Tiziana Ginex, Raimon Sabate, Belén Pérez, Vincenza Andrisano, Dolors Puigoriol-Illamola, Mercè Pallàs, F. Javier Luque, María Isabel Loza, José Brea, Isidro Ferrer, Francisco Ciruela, Angel Messeguer, Diego Muñoz-Torrero
Oxidative
stress is a major pathogenic factor in Alzheimer’s
disease, but it should not be tackled alone rather together with other
key targets to derive effective treatments. The combination of the
scaffold of the polar antioxidant lead 7-methoxy-2,2-dimethylchroman-6-ol
(CR-6) with that of the lipophilic cholinesterase inhibitor 6-chlorotacrine
results in compounds with favorable brain permeability and multiple
activities in vitro (acetylcholinesterase, butyrylcholinesterase,
β-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE-1),
and Aβ42 and tau aggregation inhibition). In in vivo studies
on wild-type and APP/presenilin 1 (PS1) mice, two selected compounds
were well tolerated and led to positive trends, albeit statistically
nonsignificant in some cases, on memory performance, amyloid pathology
(reduced amyloid burden and potentiated non-amyloidogenic APP processing),
and oxidative stress (reduced cortical oxidized proteins and increased
antioxidant enzymes superoxide dismutase 2 (SOD2), catalase, glutathione
peroxidase 1 (GPX1), and heme oxygenase 1 (Hmox1) and transcription
factor nuclear factor-erythroid 2-related factor 2 (Nrf2)). These
compounds emerge as interesting brain-permeable multitarget compounds,
with a potential as anti-Alzheimer agents beyond that of the original
lead CR-6.