Background: Parkinson’s disease (PD) is a common selective and
progressive neurodegenerative disorder of nigrostriatal dopaminergic (DA)
neurons. Quercetin is a bioflavonoid with antioxidant, anti-inflammatory,
anti-aging and anti-cancer properties. However, the exact mechanism by which
quercetin exerts its protective effect on DAergic neurons remains unclear.
Purpose: To investigate the underlying molecular mechanism of
quercetin’s protective effect on DA neurons using 1-methyl-4-phenylpyridinium (MPP)-induced PD
ferroptosis model in vitro. Methods: MPP was used to
induce cytotoxicity in SH-SY5Y/primary neurons. Cell viability and apoptosis were
assessed by CCK-8 assay and flow cytometry. The expression levels of
ferroptosis-related proteins (NCOA4, SLC7A11, Nrf2, and GPX4) were determined by
Western blotting. Malondialdehyde (MDA), iron, and GPX4 levels were assesed using
corresponding assay kits. Lipid peroxidation was assessed by C11-BODIPY staining.
Results: In the MPP-induced ferroptosis model of SH-SY5Y
cells, the expressions of SLC7A11 and GPX4 were inhibited, and the expression of
NCOA4 protein was increased, causing the overproduction of MDA and lipid
peroxidation. Quercetin can reduce the above changes caused by
MPP, that is, reduce the protein expression of NCOA4 in SH-SY5Y
cells, increase SLC7A11 and GPX4 partially inhibited by MPP, and
reduce MDA overproduction and lipid peroxidation to protect DA neurons. Nrf2
inhibitor ML385 could inhibit quercetin-induced increase of GPX4 and SLC7A11
protein expression, indicating that the protective effect of quercetin was
mediated through Nrf2. Conclusions: The results of this study suggest
that quercetin regulates ferroptosis through Nrf2-dependent signaling pathways,
thereby inhibiting MPP-induced neurotoxicity in SH-SY5Y/primary
neurons.