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Updated: May 24, 2025
Chemogenetic Regulation in Reprogrammed Stem Cell-derived Precursor Cells in Treating Neurodegenerative Diseases
Published on: May 2, 2025
Novel donepezil-tacrine hybrid (TAHB3) induces neurodifferentiation, neuroprotective effects, and activates the
Renata Melo Dos Santos Ono1, Natália Chermont Dos Santos Moreira1, Ivone Carvalho2
1Department of Genetics, Ribeirão Preto Medical School, University of São Paulo-USP, Brazil.
Background:
Alzheimer's disease (AD) is a neurodegenerative disease characterized by the impairment of cognitive functions and neuronal loss. AD has no cure; current treatments like acetylcholinesterase inhibitors (AChEI) alleviate symptoms but do not halt disease progression.
Objective:
We aimed to evaluate the effects and mechanisms of two novel AChEI hybrid compounds (TAHB3 and TA8Amino), regarding cytotoxicity, neuroprotection and neurodifferentiation in PC12 cells.
Methods:
The effects of TAHB3 and TA8Amino on neurodifferentiation were analyzed on PC12 cells which were treated with AChEI compounds for seven days, following morphological, and quantitative analyses to calculate the differentiation percentages, neurite length, and protein expression. Regarding cytotoxicity and neuroprotection assays, PC12 cells were differentiated into mature neurons, then treated with TAHB3 or TA8Amino, following a posttreatment with H2O2 (an inducer of oxidative damage); the analyses were performed using the XTT assay and flow cytometry.
Results:
The hybrid compound TAHB3 induced differentiation of PC12 cells, but TA8Amino did not cause the same effect. Both compounds did not show cytotoxic effects to PC12 cells and did not change the cell cycle progression, nor induce cell death. Only TAHB3 showed neuroprotective potential against induced-oxidative damage, and TAHB3 increased the levels of p-AKT, suggesting its action through the activation of the PI3K/AKT pathway.
Conclusions:
Our results showed that TAHB3 can induce neurodifferentiation, besides a neuroprotective activity, indicating the potential of AChEI hybrid compounds as novel candidates to be explored for the establishment of novel therapeutic strategies for patients with AD.
