Prenylated Flavanone Isolated from Dalea Species as a Potential Multitarget-Neuroprotector in an In Vitro Alzheimer’s Disease Mice Model

SANTI, MARIA D.; CARVALHO, DIEGO; DAPUETO, ROSINA; BENTURA, MANUELA; ZENI, MAIA; MARTÍNEZ-GONZÁLEZ, LORETO; MARTÍNEZ, ANA; PERALTA, MARIANA A.; REY, ANA; GIGLIO, JAVIER; ORTEGA, MARIA G.; SAVIO, EDUARDO; ABIN-CARRIQUIRY, JUAN A.; ARREDONDO, FLORENCIA

NEUROTOXICITY RESEARCH

SPRINGER

Lugar: Berlin; Año: 2024 vol. 42

1029-8428

Alzheimer’sdisease(AD)involvesaneurodegenerativeprocessthathasnotyetbeenprevented,reversed,orstopped.Continuingwiththesearchfornaturalpharmacologicaltreatments,flavonoidsareafamilyofcompoundswithprovenneuroprotectiveeffectsandmulti-targetingbehavior.TheAmericangenusDaleaL.(Fabaceae)isanimportantsourceofbioactiveflavonoids.Inthisopportunity,wetestedtheneuroprotectivepotentialofthreeprenylatedflavanonesisolatedfromDaleaspeciesinanewinvitropre-clinicalADmodelpreviouslydevelopedbyus.Ourapproachconsistedinexposingneuralcellstoconditionedmedia(3xTg-AD ACM)fromneurotoxicastrocytesderivedfromhippocampiandcorticesofold3xTg-ADmice,mimickingalocalneurodegenerativemicroenvironment.Flavanone1 and 3showedaneuroprotectiveeffectagainst3xTg-AD ACM,being1moreactivethan3.Thestructuralrequirementstoaffordneuroprotectiveactivityinthismodelarea5’-dimethylallyland4’-hydroxyattheBring.Inordertosearchthemechanisticperformanceofthemostactiveflavanone,wefocusontheflavonoid-mediatedregulationofGSK-3β-mediatedtauphosphorylationpreviouslyreported.Flavanone1treatmentdecreasedtheriseofhyperphosphorylatedtauproteinneuronallevelsinducedafter3xTgAD ACMexposureandinhibitedtheactivityofGSK-3β.Finally,directexposureoftheseneurotoxic3xTg-ADastrocytestoflavanone1resultedintoxicitytothesecellsandreducedtheneurotoxicityof3xTg-ADACMaswell.Ourresultsallowustopresentcompound1asanaturalprenylatedflavanonethatcouldbeusedasaprecursortodevelopmentanddesignoffuturedrugtherapiesforAD.