Abstract
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 (H(2)O(2))-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 H(2)O(2). 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 H(2)O(2), 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.