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

Abstract

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.

Effects of mechanical stress on human oral mucosa‐derived cells

“…Consistent with our findings, other studies also reported that MS induces the expression of RANKL via p38 in osteoblasts derived from alveolar bone and that electrical stimulation increases the level of phosphor-p38 and ERK1/2 in nerve cells (Yamamoto et al, 2015).…”

Analysis of the Differential Gene and Protein Expression Profiles of Corneal Epithelial Cells Stimulated with Alternating Current Electric Fields

“…Further, DC-induced activation of the PI3K/AKT pathway was also reported in different cell types, including neural progenitor cells [47], Schwann cells [48], and human umbilical vein endothelial cells (HUVEC) [49], as well as in ocular cells, including the corneal epithelium [6,50]. Activation of the MAPK signaling pathway is also reported through the application of EFs in neuronal cells [51,52], fibroblasts, HUVEC [53], and corneal epithelial cells [6]. Likewise, we also observed activation of PI3K/AKT and MAPK signaling pathways, along with other interconnected pathways, including T cell receptor signaling, Toll-like receptor signaling, TNF signaling, IL-17 signaling, FoxO signaling, and focal adhesion pathways, upon stimulation of corneal epithelial cells with oscillating EFs.…”

Neuromodulation for Peripheral Nerve Regeneration: Systematic Review of Mechanisms and In Vivo Highlights

“…Animal RCTs were included to examine other independent variables that have not yet been analyzed in humans. A total of 52 articles were selected for inclusion, with 45 studies [ 8 , 11 , 26 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ] on mechanisms and seven RCTs [ 73 , 74 , 75 , 76 , 77 ...…”