Structure-activity relationship and pathway of antioxidant shrimp peptides in a PC12 cell model

[Display omitted] •Two peptides from SPH were purified and identified by UPLC-Q-TOF-MS.•The peptides MTTNL and MTTNI were proved to have antioxidant activity.•The amino acid of Leu was more important than Ile in the antioxidant activity.•The activation of PI3K/Akt could protect PC12 cells from oxidative stress. This study aimed to investigate that the antioxidant capacity of the peptides Met-Thr-Thr-Asp-Ile (MTTNI) and Met-Thr-Thr-Asp-Leu (MTTNL) purified from shrimp protein hydrolysate (SPH), identified by UPLC-Q-TOF-MS, and the related signaling pathways that inhibit oxidative stress. The results indicated that the inhibition ratios of MTTNI and MTTNL hydroxyl radical scavenging activities were 10.71 ± 3.27% and 8.94 ± 0.97%, respectively, and those of their DPPH radical scavenging activities were 43.21 ± 3.55% and 38.74 ± 2.82%, respectively. The two peptides significantly decreased ROS content in PC12 cells and upregulated SOD activity to the level of the scopolamine group. Moreover, MTTNL and MTTNI could modulate oxidative stress in vitro, and the presence of Leu in the peptide sequence may be the critical factor contributing to stronger antioxidant activity than peptide sequences with Ile. MTTNL western blot analysis showed Leu suppresses Bax, Caspase-3, and p53 expression, as well as BCL-XL overexpression, thus protecting PC12 cells from oxidative stress. Overall, the peptides protected neurons from oxidative damage through the anti-apoptotic pathway.