Electrical stimulation with periodic alternating intervals stimulates neuronal cells to produce neurotrophins and cytokines through activation of mitogen‐activated protein kinase pathways

Peripheral neuropathy is a representative complication of dental surgery. Electrical therapy, based on electrical stimulation with periodic alternating intervals ( ES ‐ PAI ), may promote nerve regeneration after peripheral nerve injury in a non‐invasive manner, potentially providing an effective therapy for neuropathy. This study aimed to analyze the molecular mechanisms underlying the nerve recovery stimulated by ES ‐ PAI . In brief, ES ‐ PAI was applied to a neuronal cell line, Neuro2A, at various intensities using the pulse generator apparatus, FREUDE . Cell viability, neurotrophin mRNA expression, and cytokine production were examined using a tetrazolium‐based assay, real‐time RT ‐ PCR , and ELISA , respectively. Mitogen‐activated protein kinase ( MAPK ) signaling was assessed using flow cytometry. It was found that ES ‐ PAI increased the viability of cells and elevated expression of nerve growth factor ( NGF ) and neurotrophin‐3 ( NT ‐3); ESPAI also augmented vascular endothelial growth factor ( VEGF ) and platelet‐derived growth factor ( PDGF ) expression, which was restored by addition of p38 inhibitors. Phosphorylation of p38 and extracellular signal‐regulated kinase 1/2 ( ERK ‐1/2) was augmented by ES ‐ PAI . Hence, ES ‐ PAI may ameliorate peripheral neuropathy by promoting neuronal cell proliferation and production of neurogenic factors by activating p38 and ERK ‐1/2 pathways.