Florencia Arredondo

Natural products play a crucial role in drug discovery, primarily due to their structural complexity. The prenylated flavanone glabranin ((S)-5,7-dihydroxy-8-(3-methylbut-2-en-1-yl)-2-phenylchroman-4-one), isolated from the Dalea elegans plant species, has demonstrated neuroprotective effects, attributed to its inhibition of GSK-3β, as per our previous in silico studies. Given the enzyme’s diverse functions and its potential as a target for neurodegenerative diseases, our group synthesized and evaluated an ¹¹C-labeled derivative of glabranin. We present its in vitro biological activity, including IC₅₀, neuronal uptake in Alzheimer’s-affected brain regions, key physicochemical properties, and animal studies. This study confirms [¹¹C]FLA’s interaction with GSK-3β in vitro, highlighting the potential of radiotracers in bioactive compound research.

Natural products play a crucial role in drug discovery, primarily due to their structural complexity. The prenylated flavanone, glabranin ((S)-5,7-dihydroxy-8-(3-methylbut-2-en-1-yl)-2-phenylchroman-4-one), isolated plant Dalea elegans, has demonstrated neuroprotective effects, attributed to its inhibition of GSK-3β as per our previous in silico studies. Given the enzyme's diverse functions and its potential as a target for neurodegenerative diseases, our group synthesized and evaluated an 11C-labeled derivative of glabranin. We present its in vitro biological activity, including IC50, neuronal uptake in Alzheimer’s-affected brain regions, key physicochemical properties, and animal studies. This study confirms [11C]FLA's interaction with GSK-3β in vitro, highlighting the potential of radiotracers in bioactive compound research.

Alzheimer’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 proven neuroprotective effects and multi-targeting behavior. The American genus Dalea L. (Fabaceae) is an important source of bioactive flavonoids. In this opportunity, we tested the neuroprotective potential of three prenylated flavanones isolated from Dalea species in a new in vitro pre-clinical AD model previously developed by us. Our approach consisted in exposing neural cells to conditioned media (3xTg-AD ACM) from neurotoxic astrocytes derived from hippocampi and cortices of old 3xTg-AD mice, mimicking a local neurodegenerative microenvironment. Flavanone 1 and 3 showed a neuroprotective effect against 3xTg-AD ACM, being 1 more active than 3. The structural requirements to afford neuroprotective activity in this model are a 5’-dimethylallyl and 4’-hydroxy at the B ring. In order to search the mechanistic performance of the most active flavanone, we focus on the flavonoid-mediated regulation of GSK-3β-mediated tau phosphorylation previously reported. 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 astrocytes to flavanone 1 resulted in toxicity to these cells and reduced the neurotoxicity of 3xTg-AD ACM as well. Our results allow us to present compound 1 as a natural prenylated flavanone that could be used as a precursor to development and design of future drug therapies for AD.

Neurodegenerative diseases such as Alzheimer’s disease have been classically studied from a purely neuronocentric point of view. More recent evidences support the notion that other cell populations are involved in disease progression. In this sense, the possible pathogenic role of glial cells like astrocytes is increasingly being recognized. Once faced with tissue damage signals and other stimuli present in disease environments, astrocytes suffer many morphological and functional changes, a process referred as reactive astrogliosis. Studies from murine models and humans suggest that these complex and heterogeneous responses could manifest as disease-specific astrocyte phenotypes. Clear understanding of disease-associated astrocytes is a necessary step to fully disclose neurodegenerative processes, aiding in the design of new therapeutic and diagnostic strategies. In this work, we present the transcriptomics characterization of neurotoxic astrocytic cultures isolated from adult symptomatic animals of the triple transgenic mouse model of Alzheimer’s disease (3xTg-AD). According to the observed profile, 3xTg-AD neurotoxic astrocytes show various reactivity features including alteration of the extracellular matrix and release of pro-inflammatory and proliferative factors that could result in harmful effects to neurons. Moreover, these alterations could be a consequence of stress responses at the endoplasmic reticulum and mitochondria as well as of concomitant metabolic adaptations. Present results support the hypothesis that adaptive changes of astrocytic function induced by a stressed microenvironment could later promote harmful astrocyte phenotypes and further accelerate or induce neurodegenerative processes.