Neuroprotective Effects of Sargassum horneri Polyphenols on Rotenone-Induced SH-SY5Y Cell Injury

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Abstract Parkinson's disease (PD) is closely associated with mitochondrial dysfunction and oxidative stress. Sargassum horneri polyphenols (SHPP), as a marine-derived natural active substance, have potential neuroprotective effects, but their efficacy and mechanisms in PD models remain unclear. In this study, SH-SY5Y cells were first differentiated with all-trans-retinoic acid (ATRA) and then treated with rotenone to establish an in vitro Parkinson's disease injury model. The protective effects of SHPP were systematically evaluated, and its mechanism of action was preliminarily explored using transcriptomics. Results showed that SHPP intervention dose-dependently ameliorated rotenone-induced cell injury: cell viability in the medium- and high-dose groups was restored to 71.6% and 73.3% of the control level, ATP content to 71.2% and 74.6%, and mitochondrial complex I activity to 67.5% and 71.3%, respectively. In the high-dose group, reactive oxygen species (ROS) level decreased to 81.2% of the model group level, malondialdehyde (MDA) decreased to 68.7% of the model group level, and superoxide dismutase (SOD) activity and reduced glutathione (GSH) content was restored to 83.7% and 82.8% of the control level, respectively. In terms of apoptosis regulation, SHPP down-regulated Bax, up-regulated Bcl-2, decreased the Bax/Bcl-2 ratio, and reduced cytoplasmic cytochrome c (by 14.3%) and Cleaved Caspase-3 (by 13.6%) levels. Meanwhile, SHPP reduced the secretion of pro-inflammatory factors TNF-α, IL-6, and IL-1β, and down-regulated BAX mRNA expression while up-regulating BCL2 , NFE2L2 , and HMOX1 mRNA expression. Transcriptomic analysis revealed that only 28 differentially expressed genes were identified after SHPP intervention, of which 8 were common differentially expressed genes between the model and treatment groups (including TMEM102 , MIR34AHG , etc.), indicating that SHPP does not function by broadly altering gene expression but rather acts precisely on core genes in the disease model. In conclusion, SHPP exerts neuroprotective effects against rotenone-induced SH-SY5Y cell injury by restoring mitochondrial function, alleviating oxidative stress, inhibiting mitochondria-mediated apoptosis, and reducing neuroinflammation, providing experimental evidence for the potential application of S. horneri polyphenols in the prevention and treatment of Parkinson's disease.

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