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  • To clarify the mechanisms of

    2019-04-25

    To clarify the mechanisms of nerve regeneration by electrical stimulation, we investigated differentiation and cellular damage of drug-hypersensitive PC12m3 mutant Radicicol Supplier caused by electrical stimulation. We obtained PC12m3 cells from a variant cell line of PC12 cells that spontaneously showed impaired NGF-induced neurite outgrowth by culturing for 2 weeks under an acidic condition of Cl¯ [13]. PC12m3 cells showed poor neurite outgrowth despite normal sustained activation of ERK by NGF treatment. However, neurite outgrowth of PC12m3 cells was stimulated by various drugs including d-limonene, the immunosuppressant FK506, c-AMP and calcimycin in the presence of NGF [[13], [14], [15]]. Furthermore, treatment of PC12m3 cells with stressful stimuli such as microwave irradiation, osmotic shock, and heat shock in the presence of NGF had strong stimulatory effects on neurite outgrowth [[16], [17], [18]]. PC12m3 cells also exhibited sustained activation of p38 MAPK in response to various stimulants. In this study, we found that electrical stimulation at 100 mA for 30 min induced enhancement of neurite outgrowth of PC12m3 cells without any damage to the cells. Furthermore, p38 MAPK was strongly activated in PC12m3 cells exposed to electrical stimulation. We also found that electrical stimulation rapidly activated the transcription factor CREB in PC12m3 cells.
    Materials and methods
    Results
    Discussion Electrical stimulation can activate various biostimulatory responses in a range of tissues. Kim et al. examined osteogenesis and cytokine production in human mesenchymal stromal cells (hMSCs). When hMSCs were exposed to 100 Hz of electrical stimulation with a magnitude of 1.5/15 μA /cm2 for 250/25 μs over a period of 5 days, the cells showed increased proliferation during stimulation. Treatment with a selective inhibitor of p38 MAPK, SB203580, reduced cytokine production and cell proliferation [19]. These findings indicated the possibility that electrical stimulation is involved in the osteoblast differentiation of hMSCs through the activation of p38 MAPK. Furthermore, Zhao et al. found that exposure of both keratinocytes and neutrophils to electric fields in a serum-free medium induced rapid and sustained phosphorylation of p38 MAPK [20]. We found that p38 MAPK was activated by electrical stimulation and induced neurite outgrowth in PC12m3 cells. We also found that neurite outgrowth induced by electrical stimulation was inhibited by a specific p38 MAPK inhibitor, SB203580, in the presence of NGF in PC12m3 cells. These findings indicate that the p38 MAPK pathway plays a key role in neuronal differentiation of PC12m3 cells. Morooka and Nishida showed that activation of p38 MAPK was involved in neuronal differentiation of PC12 cells [21]. Temporin et al. found that expression of the pro-inflammatory cytokine interleukin-1 beta promotes neurite outgrowth by deactivating RhoA via the p38 MAPK pathway in cerebellar granule neurons [22]. Several lines of evidence suggest that brain-derived neurotrophic factor (BDNF) is associated with the formation, storage and recall of memory in the hippocampus and that activation of p38 MAPK is required for in vivo BDNF production in the rat hippocampus [23]. Furthermore, it has been shown that p38 MAPK is activated during associative learning and that its activation leads to memory consolidation in rabbits [24]. Hampson et al. reported that electrical stimulation delivered to hippocampal CA1 neurons enhanced human short-term/working memory by 37% during a task [25]. The results of those studies and our study suggest that electrical stimulation may improve stroke and promote memory by neurite outgrowth formation via the p38 MAPK pathway. We found that neural factors from rats undergoing electric intracranial self-stimulation to the medial forebrain bundle in the lateral hypothalamus activate the p38 MAPK pathway in PC12m3 cells [26]. We have an experimental plan to examine electrical stimulation-induced p38 MAPK activation in the hippocampus in which an electrode is implanted in order to clarify the relationship between p38 MAPK activation by electrical stimulation and memory.