Parkinson's disease (PD) is recognized as a degenerative and debilitating neurodegenerative disorder. The novel protective role of icariside II (ICS II) as a plant-derived flavonoid compound in neurodegenerative diseases has aroused much attention. Herein, the definite impacts of ICS II on the process of PD and the relevant action mechanism were studied. Human neuroblastoma SK-N-SH cells were challenged with 1-methyl-4-phenylpyridinium ion (MPP+) to construct the PD cell model. MTT assay and flow cytometry analysis, respectively, appraised cell viability and apoptosis. Caspase 3 Activity Assay examined caspase 3 activity. Corresponding kits examined oxidative stress levels. BODIPY 581/591 C11 assay evaluated lipid reactive oxygen species. Iron Assay Kit assessed iron content. Western blot tested the expression of apoptosis-, ferroptosis- and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling-associated proteins. Molecular docking verified the binding of ICS II with Keap1. The existing experimental results unveiled that ICS II elevated the viability whereas reduced the apoptosis, oxidative stress, and ferroptosis in MPP+-treated SK-N-SH cells in a concentration-dependent manner. Furthermore, ICS II declined Keap1 expression while raised Nrf2, heme oxygenase 1, and GPX4 expression. In addition, ICS II had a strong binding with Keap1 and Nrf2 inhibitor ML385 partially abolished the suppressive role of ICS II in MPP+-triggered apoptosis, oxidative stress, and ferroptosis in SK-N-SH cells. To summarize, ICS II might inhibit apoptosis, oxidative stress, and ferroptosis in the MPP+-stimulated PD cell model, which might be due to the activation of Keap1/Nrf2/GPX4 signaling.
