Abstract
The activation of NADPH oxidase contributes to dopaminergic neurodegeneration induced by paraquat and maneb, two concurrently used pesticides in agriculture. However, the mechanisms remain unclear. Ferroptosis, a recently recognized form of regulated cell death, has been implicated in the pathogenesis of multiple neurodegenerative diseases. This study is designed to investigate whether ferroptosis is involved in NADPH oxidase-regulated dopaminergic neurotoxicity. In vitro study showed that paraquat and maneb exposure induced ferroptosis in SHSY5Y dopaminergic cells, which was associated with activation of NADPH oxidase. Inhibition of NADPH oxidase by apocynin or diphenyleneiodonium (DPI), two widely used NADPH oxidase inhibitors mitigated paraquat and maneb-induced ferroptotic cell death. Consistently, stimulating activation of NADPH oxidase by phorbol myristate acetate (PMA) or supplementation of H2O2 exacerbated ferroptosis in paraquat and maneb-treated SHSY5Y cells. Mechanistic inquiry revealed that NADPH oxidase activation elicited lipid peroxidation, a main driving force for ferroptosis, since both apocynin and DPI greatly reduced MDA contents and simultaneously recovered levels of glutathione and glutathione peroxidase 4 ...Continue Reading
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