High-Frequency, Low-Intensity Pulsed Electric Field and N-Acetylcysteine Synergistically Protect SH-SY5Y Cells Against Hydrogen Peroxide-Induced Cell Damage In Vitro

Oxidative stress plays an important role in the progression of neurodegenerative diseases (NDDs), and N-acetylcysteine (NAC) has gained attention as a potential agent due to its antioxidant capabilities. This study investigated the synergistic neuroprotective effects of combining NAC with non-contact, high-frequency, low-intensity pulsed electric field (H-LIPEF) stimulation on SH-SY5Y human neuronal cells subjected to hydrogen peroxide (H₂O₂)-induced oxidative damage. It was found that after SH-SY5Y cells were pretreated with NAC and exposed to H-LIPEF stimulation, the oxidative stress of cells was reduced in the subsequent treatment with H₂O₂. The results showed that the combined NAC and H-LIPEF treatment significantly improved cell viability and more effectively reduced mitochondrial apoptosis. Mechanistic analyses revealed that the combination substantially decreased levels of superoxide and intracellular H₂O₂, which was associated with enhanced activation of the phosphorylated Akt (p-Akt)/nuclear factor erythroid 2-related factor 2 (Nrf2)/superoxide dismutase type 2 (SOD2) signaling pathway. Furthermore, the treatment reduced the accumulation of 8-oxo-2'-deoxyguanosine triphosphate (8-oxo-dG) accumulation and elevated MutT homolog 1 (MTH1) expression, indicating a protective effect against oxidative DNA damage. These results suggest that H-LIPEF enhances the neuroprotective efficacy of low-dose NAC, highlighting the potential of this combination approach as a new therapeutic strategy for the treatment of NDDs.