Neuroprotective Function of a Novel Hexapeptide QMDDQ from Shrimp via Activation of the PKA/CREB/BNDF Signaling Pathway and Its Structure–Activity Relationship

This study aimed to evaluate the neuroprotective function of shrimp-derived peptides QMDDQ and KMDDQ. Biochemical results revealed that both peptides exhibited neuroprotective effects by increasing acetylcholine (ACh) content and inhibiting acetylcholinesterase (AChE) activity in PC12 cells; QMDDQ was more active than KMDDQ. COSY-NOESY spectroscopic data showed that the superior neuroprotective function of QMDDQ might be attributed to its N-terminal glutamine as it exhibited an extended spatial conformation, facilitating its interactions with AChE. QMDDQ can promote the basic energy metabolism of cells more than KMDDQ. The peptides showed neuroprotective ability due to the activation of the antiapoptosis and PKA/CREB/BNDF signaling pathway. QMDDQ was selected to investigate its memory-enhancing activity in scopolamine-induced amnesic mice, revealing memory protection in mice, as it improved their performance in the Morris water maze experiment. In addition, QMDDQ increased ACh content (4.98 ± 0.51 μg/mg prot) and decreased AChE activity (4.72 ± 0.11 U/mg prot) in the mouse hippocampus. These data indicate the systemic mechanism through which naturally derived QMDDQ improved neuroprotection and memory ability.