{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T02:18:15Z","timestamp":1778984295534,"version":"3.51.4"},"reference-count":43,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2017,2,16]],"date-time":"2017-02-16T00:00:00Z","timestamp":1487203200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"DOD","doi-asserted-by":"publisher","award":["W81XWH-13-2-0052"],"award-info":[{"award-number":["W81XWH-13-2-0052"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 (eIF2\u03b1), and enhanced activating transcription factor 4 (ATF4) in an energy-dependent manner. In addition, GSK2656157\u2014an inhibitor of PERK\u2014effectively inhibited the effect of Li-ESWT on the phosphorylation of PERK, eIF2\u03b1, 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)1\u03b1 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.<\/jats:p>","DOI":"10.3390\/ijms18020433","type":"journal-article","created":{"date-parts":[[2017,2,16]],"date-time":"2017-02-16T12:55:34Z","timestamp":1487249734000},"page":"433","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Low-Intensity Extracorporeal Shock Wave Therapy Enhances Brain-Derived Neurotrophic Factor Expression through PERK\/ATF4 Signaling Pathway"],"prefix":"10.3390","volume":"18","author":[{"given":"Bohan","family":"Wang","sequence":"first","affiliation":[{"name":"Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongxiu","family":"Ning","sequence":"additional","affiliation":[{"name":"Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Reed-Maldonado","sequence":"additional","affiliation":[{"name":"Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yajun","family":"Ruan","sequence":"additional","affiliation":[{"name":"Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tie","family":"Zhou","sequence":"additional","affiliation":[{"name":"Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsun","family":"Wang","sequence":"additional","affiliation":[{"name":"Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Byung","family":"Oh","sequence":"additional","affiliation":[{"name":"Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lia","family":"Banie","sequence":"additional","affiliation":[{"name":"Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7518-0788","authenticated-orcid":false,"given":"Guiting","family":"Lin","sequence":"additional","affiliation":[{"name":"Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom","family":"Lue","sequence":"additional","affiliation":[{"name":"Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.eururo.2006.10.043","article-title":"Upregulation of penile brain-derived neurotrophic factor (BDNF) and activation of the JAK\/STAT signalling pathway in the major pelvic ganglion of the rat after cavernous nerve transection","volume":"52","author":"Bella","year":"2007","journal-title":"Eur. Urol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1111\/j.1743-6109.2006.00291.x","article-title":"Brain-derived neurotrophic factor (BDNF) acts primarily via the JAK\/STAT pathway to promote neurite growth in the major pelvic ganglion of the rat: Part I","volume":"3","author":"Bella","year":"2006","journal-title":"J. Sex. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1111\/j.1743-6109.2006.00292.x","article-title":"Brain-derived neurotrophic factor (BDNF) acts primarily via the JAK\/STAT pathway to promote neurite growth in the major pelvic ganglion of the rat: Part 2","volume":"3","author":"Lin","year":"2006","journal-title":"J. Sex. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1046\/j.1464-410X.2003.04373.x","article-title":"The effect of vascular endothelial growth factor and brain-derived neurotrophic factor on cavernosal nerve regeneration in a nerve-crush rat model","volume":"92","author":"Hsieh","year":"2003","journal-title":"BJU Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1016\/S0022-5347(05)66302-1","article-title":"The effect of adeno-associated virus mediated brain derived neurotrophic factor in an animal model of neurogenic impotence","volume":"165","author":"Bakircioglu","year":"2001","journal-title":"J. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.neubiorev.2015.04.017","article-title":"BDNF Val66Met polymorphism and hippocampal volume in neuropsychiatric disorders: A systematic review and meta-analysis","volume":"55","author":"Harrisberger","year":"2015","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Martinotti, G., Pettorruso, M., de Berardis, D., Varasano, P.A., Lucidi Pressanti, G., de Remigis, V., Valchera, A., Ricci, V., di Nicola, M., Janiri, L., Biggio, G., and Di Giannantonio, M. (2016). Agomelatine increases BDNF serum levels in depressed patients in correlation with the improvement of depressive symptoms. Int. J. Neuropsychopharmacol., 19.","DOI":"10.1093\/ijnp\/pyw003"},{"key":"ref_8","first-page":"347","article-title":"Nerve growth factor and brain-derived neurotrophic factor concentrations in schizophrenia: A review","volume":"26","author":"Martinotti","year":"2012","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Campos, C., Rocha, N.B., Nardi, A.E., Lattari, E., and Machado, S. (2016). Exercise induced neuroplasticity to enhance therapeutic outcomes of cognitive remediation in Schizophrenia: Analyzing the role of brain-derived neurotrophic factor. CNS Neurol. Disord. Drug Targets.","DOI":"10.2174\/1871527315666161223142918"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e985","DOI":"10.1038\/tp.2016.227","article-title":"Brain-derived neurotrophic factor increase during treatment in severe mental illness inpatients","volume":"6","author":"Nuernberg","year":"2016","journal-title":"Transl. Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1074\/jbc.M111.312736","article-title":"Brain-derived neurotrophic factor (BDNF) induces polarized signaling of small GTPase (Rac1) protein at the onset of Schwann cell myelination through partitioning-defective 3 (Par3) protein","volume":"287","author":"Tep","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1016\/j.eururo.2008.02.003","article-title":"GDNF-transduced Schwann cell grafts enhance regeneration of erectile nerves","volume":"54","author":"May","year":"2008","journal-title":"Eur. Urol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1177\/1071100712464354","article-title":"The effectiveness of extracorporeal shock wave therapy on chronic achilles tendinopathy: A systematic review","volume":"34","author":"Simon","year":"2013","journal-title":"Foot Ankle Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"295","DOI":"10.2165\/11592760-000000000-00000","article-title":"Extracorporeal shock wave therapy for ischemic cardiovascular disorders","volume":"11","author":"Ito","year":"2011","journal-title":"Am. J. Cardiovasc. Drugs"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1111\/j.1743-6109.2011.02498.x","article-title":"Low-intensity extracorporeal shock wave therapy\u2014A novel effective treatment for erectile dysfunction in severe ED patients who respond poorly to PDE5 inhibitor therapy","volume":"9","author":"Gruenwald","year":"2012","journal-title":"J. Sex. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0304-3940(01)02320-5","article-title":"Shock wave application to rat skin induces degeneration and reinnervation of sensory nerve fibres","volume":"315","author":"Ohtori","year":"2001","journal-title":"Neurosci. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.autneu.2006.04.003","article-title":"Extracorporeal shockwaves induce the expression of ATF3 and GAP-43 in rat dorsal root ganglion neurons","volume":"128","author":"Murata","year":"2006","journal-title":"Auton Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1111\/jsm.12024","article-title":"Effects of low-energy shockwave therapy on the erectile function and tissue of a diabetic rat model","volume":"10","author":"Qiu","year":"2013","journal-title":"J. Sex. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"208","DOI":"10.5534\/wjmh.2013.31.3.208","article-title":"Low-intensity shock wave therapy and its application to erectile dysfunction","volume":"31","author":"Lei","year":"2013","journal-title":"World J. Mens. Health"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jsxm.2015.11.008","article-title":"Low-energy shock wave therapy ameliorates erectile dysfunction in a pelvic neurovascular injuries rat model","volume":"13","author":"Li","year":"2016","journal-title":"J. Sex. Med."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Bahar, E., Kim, H., and Yoon, H. (2016). ER stress-mediated signaling: Action potential and Ca2+ as key players. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17091558"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1083\/jcb.153.5.1011","article-title":"Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2\u03b1","volume":"153","author":"Novoa","year":"2001","journal-title":"J. Cell. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.neuroscience.2005.01.019","article-title":"Neurotrophin-3 is a target-derived neurotrophic factor for penile erection-inducing neurons","volume":"133","author":"Hiltunen","year":"2005","journal-title":"Neuroscience"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1007\/s00018-006-6010-1","article-title":"Neurotrophin signaling: Many exciting surprises!","volume":"63","author":"Arevalo","year":"2006","journal-title":"Cell Mol. Life Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.conb.2005.01.004","article-title":"p75NTR\u2014Live or let die","volume":"15","author":"Nykjaer","year":"2005","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Tanaka, K., Okugawa, Y., Toiyama, Y., Inoue, Y., Saigusa, S., Kawamura, M., Araki, T., Uchida, K., Mohri, Y., and Kusunoki, M. (2014). Brain-derived neurotrophic factor (BDNF)-induced tropomyosin-related kinase B (Trk B) signaling is a potential therapeutic target for peritoneal carcinomatosis arising from colorectal cancer. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096410"},{"key":"ref_27","first-page":"1265","article-title":"Overexpression of BDNF and TrkB in human bladder cancer specimens","volume":"24","author":"Lai","year":"2010","journal-title":"Oncol. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.lungcan.2012.07.011","article-title":"Expression of TrkB and BDNF is associated with poor prognosis in non-small cell lung cancer","volume":"78","author":"Okamura","year":"2012","journal-title":"Lung Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1016\/j.cellsig.2010.07.014","article-title":"Overexpression of p75(NTR) increases survival of breast cancer cells through p21(WAF1)","volume":"22","author":"Verbeke","year":"2010","journal-title":"Cell Signal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3521","DOI":"10.1113\/JP270874","article-title":"The repair Schwann cell and its function in regenerating nerves","volume":"594","author":"Jessen","year":"2016","journal-title":"J. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1046\/j.1460-9568.1998.00071.x","article-title":"Schwann cells genetically modified to secrete human BDNF promote enhanced axonal regrowth across transected adult rat spinal cord","volume":"10","author":"Menei","year":"1998","journal-title":"Eur. J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Lu, Z., Lin, G., Reed-Maldonado, A., Wang, C., Lee, Y.C., and Lue, T.F. (2016). Low-intensity extracorporeal shock wave treatment improves erectile function: A systematic review and meta-analysis. Eur. Urol.","DOI":"10.1016\/j.eururo.2016.05.050"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1253\/circj.CJ-14-0230","article-title":"Extracorporeal low-energy shock-wave therapy exerts anti-inflammatory effects in a rat model of acute myocardial infarction","volume":"78","author":"Abe","year":"2014","journal-title":"Circ. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/j.burns.2012.02.018","article-title":"Extracorporeal shock waves improve angiogenesis after full thickness burn","volume":"38","author":"Goertz","year":"2012","journal-title":"Burns"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1272\/jnms.81.19","article-title":"Low-energy extracorporeal shock wave therapy improves microcirculation blood flow of ischemic limbs in patients with peripheral arterial disease: Pilot study","volume":"81","author":"Tara","year":"2014","journal-title":"J. Nippon. Med. Sch."},{"key":"ref_36","first-page":"217","article-title":"Clinical application of shock wave therapy (SWT) in musculoskeletal disorders","volume":"50","author":"Ioppolo","year":"2014","journal-title":"Eur. J. Phys. Rehabil. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"167","DOI":"10.21037\/tau.2016.02.03","article-title":"Brain-derived neurotrophic factor promotes nerve regeneration by activating the JAK\/STAT pathway in Schwann cells","volume":"5","author":"Lin","year":"2016","journal-title":"Transl. Androl. Urol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"27090","DOI":"10.1074\/jbc.M114.580936","article-title":"Shock wave treatment enhances cell proliferation and improves wound healing by ATP release-coupled extracellular signal-regulated kinase (ERK) activation","volume":"289","author":"Weihs","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: From stress pathway to homeostatic regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1021\/ml400228e","article-title":"Discovery of GSK2656157: An optimized PERK inhibitor selected for preclinical development","volume":"4","author":"Axten","year":"2013","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.pharmthera.2013.01.004","article-title":"GDNF, NGF and BDNF as therapeutic options for neurodegeneration","volume":"138","author":"Allen","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"12722","DOI":"10.1073\/pnas.1002339107","article-title":"Regulation of human metabolism by hypoxia-inducible factor","volume":"107","author":"Formenti","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3331","DOI":"10.1111\/j.1743-6109.2010.01875.x","article-title":"Injections of adipose tissue-derived stem cells and stem cell lysate improve recovery of erectile function in a rat model of cavernous nerve injury","volume":"7","author":"Albersen","year":"2010","journal-title":"J. Sex. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/2\/433\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:28:24Z","timestamp":1760207304000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/2\/433"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,2,16]]},"references-count":43,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2017,2]]}},"alternative-id":["ijms18020433"],"URL":"https:\/\/doi.org\/10.3390\/ijms18020433","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,2,16]]}}}