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Download fileDiscovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice
journal contribution
posted on 2020-12-28, 09:29 authored by Elisabet Viayna, Nicolas Coquelle, Monika Cieslikiewicz-Bouet, Pedro Cisternas, Carolina A. Oliva, Elena Sánchez-López, Miren Ettcheto, Manuela Bartolini, Angela De Simone, Mattia Ricchini, Marisa Rendina, Mégane Pons, Omidreza Firuzi, Belén Pérez, Luciano Saso, Vincenza Andrisano, Florian Nachon, Xavier Brazzolotto, Maria Luisa García, Antoni Camins, Israel Silman, Ludovic Jean, Nibaldo C. Inestrosa, Jacques-Philippe Colletier, Pierre-Yves Renard, Diego Muñoz-TorreroThe
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 C57BL6 mice, with one compound
(5i) 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 Aβ42/Aβ40 ratio in the hippocampus,
improved basal synaptic efficacy, and significantly reduced hippocampal
oxidative stress and neuroinflammation. Compound 5i emerges
as an interesting anti-Alzheimer lead with beneficial effects on cognitive
symptoms and on some underlying disease mechanisms.
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antioxidant capsaicin resultsantioxidant propertiesanti-Alzheimerbutyrylcholinesterasecombinationcompoundbiodistribution studiesAPPacetylcholinesteraseChronic treatmentAntioxidant Activityhippocampuneuroinflammation4 weekshippocampal oxidative stressAcetylcholinesterasei.pAlzheimer-like pathology progressiondonepezilCompound 5 iAlleviates Alzheimer-like PathologybasisAChEmemory impairments5 iInhibitorBrain penetrationsymptommgOldBChEnanomolar potenciescholinesterase inhibitor huprine YC 57BL micecrystal structuresbasal synaptic efficacydisease mechanismscomplexpotencyButyrylcholinesterasePotentscaffold