Polyphenol-Enriched Fraction from Chestnut Shells as a Source of Bioactive Compounds for Friedreich Ataxia

We explored the ability of the low molecular weight, polyphenol-rich fractions obtained from chestnut shells to inhibit ferroptosis in Friedreich Ataxia (FRDA), an inherited neuro- and cardio-degenerative disease. We prepared an aqueous extract by an eco-sustainable method and obtained a polyphenol-rich fraction (fraction D) of molecular weight less than 1.0 kDa after molecular size fractionation. The total phenols were 173.28 ± 4.97 μg gallic acid equivalents/mg fraction, and analysis by UHPLC-ITMSⁿ and RP-HPLC-UV revealed thirteen phenolic compounds with gallic acid and protocatechuic acid (PCA) as the most abundant (26.29 ± 2.19 and 4.93 ± 0.19 μg/mg fraction, respectively). Using a cellular assay based on patient-derived FRDA fibroblasts, we observed that chestnut shell dry extract at 20 µg/mL increased the survival of cells stressed with the ferroptosis inducer erastin from 8% to 45% and that this activity was dose-dependent. Fraction D at 20 µg/mL showed similar strong activity, increasing cell survival from 0.5% to 14% and decreasing lipid peroxidation by 42%. PCA, the most efficacious compound, doubled cell survival and decreased lipid peroxidation by 20%. Moreover, PCA increased the survival of cells in which frataxin was knocked down 1.5-fold and decreased ALOX12 expression. Our data suggest that PCA could be a promising molecule to explore FRDA pathophysiology.