Grapefruit By-Products as a Sustainable Source of Bioaccessible Polyphenols with In Vitro Neuroprotective Potential.

Cognitive decline and neurodegenerative disorders represent a growing global health challenge, while effective preventive strategies remain limited. Citrus by-products, particularly grapefruit residues, constitute a rich and underexploited source of polyphenols, including flavonoids with reported antioxidant and neuroprotective properties. In this study, grapefruit-derived stabilized extract (GDSE) was evaluated using an in vitro neuronal model combined with dynamic simulated gastrointestinal digestion to assess the bioaccessibility and retained biological activity of key polyphenolic compounds. The soluble intestinal fraction of the digested formulation significantly reduced oxidative stress in dopaminergic-differentiated SH-SY5Y cells and was associated with changes in the expression of genes associated with neurotrophic support, dopaminergic signalling, and neuronal survival. In parallel, simulated digestion preserved a substantial proportion of major flavonoids, such as naringin and narirutin. Consequently, GDSE retained a moderate level of bioaccessible polyphenols and flavonoids, supporting the maintenance of its biological activity after digestion. Overall, these findings indicate that the formulation retains measurable bioactivity after simulated gastrointestinal digestion and modulates molecular markers associated with neuronal survival in vitro. While further in vivo and clinical studies are needed to fully establish its relevance for neuroprotection, the findings provide evidence that grapefruit-derived polyphenolic preparations could represent a potential source of bioactive compounds for further investigation as nutraceutical ingredients.