The Identification and Synthesis of New Sea Cucumber Peptides Leveraging Peptidomics Technology, along with their Anti-Parkinson's Disease Efficacy.

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, remains without a curative pharmacological intervention. Sea Cucumber Peptides (SCP) are recognized for their antioxidant properties and neuroprotective potential, while no specific SCP have been documented for PD treatment. Moreover, sea cucumbers have long been consumed as a traditional food; viewed through the lens of "food-medicine homology", their peptides possess clear pharmaceutical potential. This study sets out to pinpoint particular peptide sequences from sea cucumbers could combat PD, exploring their therapeutic efficacy and the underlying mechanisms. We treated Rotenone (Rot)-induced C57BL/6 J mice and SH-SY5Y cells with the SCP which were extracted from the sea cucumbers, to assess the impact on behavioral metrics in mice, histopathological outcomes, cellular viability, and in vitro bioactivity. Employing a combination of peptide profiling and silico analysis, we established a SCP spectrum to identify novel SCP with potential anti-PD activity. The therapeutic effects and mechanisms of the peptides were further investigated in 7-day-old zebrafish larvae and SH-SY5Y cells exposed in Rot, respectively. Our findings indicate that the SCP significantly improved behavioral deficits in mice, reduced the degeneration of dopaminergic neurons in the substantia nigra, and increased the survival of Rot-exposed SH-SY5Y cells. Notably, a novel peptide, Gln-Trp-Phe-Asp-Trp (QWFDW), emerged from our peptide profiling and in silico analysis, showing significant anti-PD activity. QWFDW was demonstrated to enhance the behavioral performance of Rot-induced zebrafish larvae, and ameliorate the pathological features of PD by attenuating endogenous reactive oxygen species (ROS) and maintaining mitochondrial membrane potential in SH-SY5Y cells. At the cellular level, QWFDW activates the Nrf2/HO-1/GPX4 pathway to alleviate ferroptosis and exert therapeutic effects on PD. Collectively, our results point out that SCP, particularly QWFDW, was a prospective therapeutic agent for PD.