Investigation of a Neuroprotective Peptide from Round Scad ( Decapterus maruadsi ): Bioactivity Validation, Gastrointestinal Digestion Stability, and Structure–Activity Relationship Analysis

) peptide Pro-Pro-Trp(PPW) through molecular simulations, in cellular cell model and in vivo experiments. Our results showed that PPW conferred neuroprotection in glutamate-damaged SH-SY5Y cells. PPW was resistant to gastrointestinal digestion and could transport across the Caco-2 cell monolayer via the PepT1 transporter and transcytosis pathway. The physicochemical properties of PPW, including low molecular weight and a high content of hydrophobic amino acids, were beneficial for its stability. Furthermore, PPW attenuated the cognitive decline in sleep-deprived mice, and PPW alleviated oxidative stress and neuroinflammation by activating the Akt/Nrf2 pathway and suppressing the NFκB pathway. Quantum chemistry analysis of structure-activity relationships identified the indole group of Trp as a crucial active site for the biological activity of PPW. These findings provide a basis for the application of the round scad peptide as a functional food.