Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice

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dc.contributor.authorViayna, Elisabet
dc.contributor.authorCoquelle, Nicolas
dc.contributor.authorCieslikiewicz-Bouet, Monika
dc.contributor.authorCisternas, Pedro
dc.contributor.authorOliva, Carolina A.
dc.contributor.authorSanchez-Lopez, Elena
dc.contributor.authorEttcheto, Miren
dc.contributor.authorBartolini, Manuela
dc.contributor.authorDe Simone, Angela
dc.contributor.authorRicchini, Mattia
dc.contributor.authorRendina, Marisa
dc.contributor.authorPons, Megane
dc.contributor.authorFiruzi, Omidreza
dc.contributor.authorPerez, Belen
dc.contributor.authorSaso, Luciano
dc.contributor.authorAndrisano, Vincenza
dc.contributor.authorNachon, Florian
dc.contributor.authorBrazzolotto, Xavier
dc.contributor.authorLuisa Garcia, Maria
dc.contributor.authorCamins, Antoni
dc.contributor.authorSilman, Israel
dc.contributor.authorJean, Ludovic
dc.contributor.authorInestrosa, Nibaldo C.
dc.contributor.authorColletier, Jacques-Philippe
dc.contributor.authorRenard, Pierre-Yves
dc.contributor.authorMunoz-Torrero, Diego
dc.date.accessioned2025-01-20T23:53:31Z
dc.date.available2025-01-20T23:53:31Z
dc.date.issued2021
dc.description.abstractThe combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in CS7BL6 mice, with one compound (Si) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced A beta 42/A beta 40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound Si emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.
dc.fuente.origenWOS
dc.identifier.doi10.1021/acs.jmedchem.0c01775
dc.identifier.eissn1520-4804
dc.identifier.issn0022-2623
dc.identifier.urihttps://doi.org/10.1021/acs.jmedchem.0c01775
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/94971
dc.identifier.wosidWOS:000611409600044
dc.issue.numero1
dc.language.isoen
dc.pagina.final839
dc.pagina.inicio812
dc.revistaJournal of medicinal chemistry
dc.rightsacceso restringido
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleDiscovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice
dc.typeartículo
dc.volumen64
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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