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Int. J. Mol. Sci. 2017, 18(2), 433; doi:10.3390/ijms18020433

Low-Intensity Extracorporeal Shock Wave Therapy Enhances Brain-Derived Neurotrophic Factor Expression through PERK/ATF4 Signaling Pathway

Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA
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Academic Editor: Irmgard Tegeder
Received: 30 December 2016 / Revised: 23 January 2017 / Accepted: 13 February 2017 / Published: 16 February 2017
(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor)
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Abstract

Low-intensity extracorporeal shock wave therapy (Li-ESWT) is used in the treatment of erectile dysfunction, but its mechanisms are not well understood. Previously, we found that Li-ESWT increased the expression of brain-derived neurotrophic factor (BDNF). Here we assessed the underlying signaling pathways in Schwann cells in vitro and in penis tissue in vivo after nerve injury. The result indicated that BDNF were significantly increased by the Li-ESWT after nerve injury, as well as the expression of BDNF in Schwann cells (SCs, RT4-D6P2T) in vitro. Li-ESWT activated the protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK) pathway by increasing the phosphorylation levels of PERK and eukaryotic initiation factor 2a (eIF2α), and enhanced activating transcription factor 4 (ATF4) in an energy-dependent manner. In addition, GSK2656157—an inhibitor of PERK—effectively inhibited the effect of Li-ESWT on the phosphorylation of PERK, eIF2α, and the expression of ATF4. Furthermore, silencing ATF4 dramatically attenuated the effect of Li-ESWT on the expression of BDNF, but had no effect on hypoxia-inducible factor (HIF)1α or glial cell-derived neurotrophic factor (GDNF) in Schwann cells. In conclusion, our findings shed new light on the underlying mechanisms by which Li-ESWT may stimulate the expression of BDNF through activation of PERK/ATF4 signaling pathway. This information may help to refine the use of Li-ESWT to further improve its clinical efficacy. View Full-Text
Keywords: low-intensity extracorporeal shock wave treatment; brain-derived neurotrophic factor; PERK/ATF4 pathway; Schwann cells low-intensity extracorporeal shock wave treatment; brain-derived neurotrophic factor; PERK/ATF4 pathway; Schwann cells
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Wang, B.; Ning, H.; Reed-Maldonado, A.B.; Zhou, J.; Ruan, Y.; Zhou, T.; Wang, H.S.; Oh, B.S.; Banie, L.; Lin, G.; Lue, T.F. Low-Intensity Extracorporeal Shock Wave Therapy Enhances Brain-Derived Neurotrophic Factor Expression through PERK/ATF4 Signaling Pathway. Int. J. Mol. Sci. 2017, 18, 433.

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