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

AbstractAlzheimer?s disease (AD) involves a neurodegenerative process that has not yet been prevented, reversed, or stopped.Continuing with the search for natural pharmacological treatments, flavonoids are a family of compounds with provenneuroprotective effects and multi-targeting behavior. The American genus Dalea L. (Fabaceae) is an important source ofbioactive flavonoids. In this opportunity, we tested the neuroprotective potential of three prenylated flavanones isolatedfrom Dalea species in a new in vitro pre-clinical AD model previously developed by us. Our approach consisted in exposingneural cells to conditioned media (3xTg-AD ACM) from neurotoxic astrocytes derived from hippocampi and cortices ofold 3xTg-AD mice, mimicking a local neurodegenerative microenvironment. Flavanone 1 and 3 showed a neuroprotectiveeffect against 3xTg-AD ACM, being 1 more active than 3. The structural requirements to afford neuroprotective activityin this model are a 5?-dimethylallyl and 4?-hydroxy at the B ring. In order to search the mechanistic performance of themost active flavanone, we focus on the flavonoid-mediated regulation of GSK-3β-mediated tau phosphorylation previouslyreported. Flavanone 1 treatment decreased the rise of hyperphosphorylated tau protein neuronal levels induced after 3xTg-AD ACM exposure and inhibited the activity of GSK-3β. Finally, direct exposure of these neurotoxic 3xTg-AD astrocytesto flavanone 1 resulted in toxicity to these cells and reduced the neurotoxicity of 3xTg-AD ACM as well. Our resultsallow us to present compound 1 as a natural prenylated flavanone that could be used as a precursor to development anddesign of future drug therapies for AD.Keywords Prenylated flavanones · Alzheimer?s disease · Dementia · 3xTg-AD mouse · Tau & phospho-Tau protein ·Glycogen synthase kinase 3β