Neuroprotective Effects of Zerumbone on H2O2-Induced Oxidative Injury in Human Neuroblastoma SH-SY5Y Cells

Oxidative stress is recognized as one of the main reasons for cellular damage and neurodegenerative diseases. Zerumbone is one of the sesquiterpenoid compounds in the essential oil of Zingiber zerumbet Smith. Zerumbone exhibits various physiological activities, such as anticancer, antioxidant, and antibacterial effects. However, studies on the neuroprotective efficacy of zerumbone and the mechanism behind it are lacking. In this study, we explored the neuroprotective efficacy of zerumbone and its mechanism in hydrogen peroxide-treated human neuroblastoma SH-SY5Y cells. H₂O₂ treatment (400 μM) for 24 h enhanced the generation of intracellular reactive oxygen species (ROS) compared to untreated cells. By contrast, zerumbone treatment significantly suppressed the production of intracellular ROS. Zerumbone significantly inhibited H₂O₂-induced nitric oxide production and expression of inflammation-related genes. Moreover, zerumbone decreased H₂O₂-induced mitogen-activated protein kinase (MAPK) protein expression. Various hallmarks of apoptosis in H₂O₂-treated cells were suppressed in a dose-dependent manner through downregulation of the Bax/Bcl-2 expression ratio by zerumbone. Since activation of AMP-activated kinase (AMPK) is a promising therapeutic target for neurodegenerative diseases, we also investigated the mammalian target of rapamycin (mTOR) as part of the autophagy mechanism in H₂O₂-treated SH-SY5Y cells. In this study, zerumbone upregulated the expression of Sirtuin 1 (SIRT1) and p-AMPK (which were downregulated by the H₂O₂ treatment) and downregulated p-mTOR. Altogether, our results propose that inhibition of apoptosis and inflammation by autophagy activation plays an important neuroprotective role in H₂O₂-treated SH-SY5Y cells. Zerumbone may thus be a potent dietary agent that reduces the onset and progression, as well as prevents neurodegenerative diseases.