{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:51:37Z","timestamp":1785372697656,"version":"3.55.0"},"reference-count":51,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T00:00:00Z","timestamp":1637539200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T00:00:00Z","timestamp":1637539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Neurobiol"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>We aimed to investigate the effects of endurance training on expression of growth factors (GFs) and stimulation of neurotrophin-dependent signaling pathways (PI3k\/Akt, PLC\u03b3\/PKC, PLC\u03b3\/CAMKII, Ras-Erk1\/2 and Rac1-Cdc42) responsible for neuroplasticity, neuroregeneration, survival and growth after spinal cord injury (SCI). Wistar rats were divided into four groups: (i) intact controls; (ii) 6\u00a0weeks of endurance training; (iii) SCI; (iv) pre-training\u2009+\u2009SCI. The animals survived for 6\u00a0weeks after SCI. Firstly, endurance training markedly upregulated mRNA expression and protein levels (up to four times) of growth factors (BDNF, GDNF) and their receptors (TrkB, Gfr\u03b1) in low thoracic segments (Th8\u2013Th10) compared to levels in untrained animals. Secondly, we found that spontaneous neuroplasticity seen in the SCI alone group was GF-specific and was activated through both PLC\u03b3-PKC and PLC-CAMKII signaling pathways. In addition, training prior to SCI markedly increased the activity of PLC\u03b3-PKC signaling at both transcript and protein levels at and around the lesion site. Similar effects were seen in expression of PI3k\/Akt and Ras\/Erk1\/2 signaling responsible for cell survival and regeneration. Thirdly, rats which underwent physical activity prior to SCI were more active and had significantly better neurological scores at the 14th and 42nd days of survival. These results suggest that regular physical activity could play an important role after SCI, as it maintains increased expression of GFs in spinal cord tissue 6\u00a0weeks post-SCI. The BDNF- and\/or BDNF\u2009+\u2009GDNF-dependent signaling pathways were significantly affected in pre-trained SCI animals. In contrast, GDNF-dependent Rac1-Cdc42 signaling was not involved in training-affected SCI response.<\/jats:p>","DOI":"10.1007\/s12035-021-02628-y","type":"journal-article","created":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T18:02:30Z","timestamp":1637604150000},"page":"950-967","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Activation of Three Major Signaling Pathways After Endurance Training\u00a0and Spinal Cord Injury"],"prefix":"10.1007","volume":"59","author":[{"given":"Katarina","family":"Kiss Bimbova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Bacova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Kisucka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Galik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Zavacky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8834-6852","authenticated-orcid":false,"given":"Nadezda","family":"Lukacova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,22]]},"reference":[{"key":"2628_CR1","doi-asserted-by":"publisher","first-page":"282","DOI":"10.3389\/fneur.2019.00282","volume":"10","author":"A Alizadeh","year":"2019","unstructured":"Alizadeh A, Dyck SM, Karimi-Abdolrezaee S (2019) Traumatic spinal cord injury: an overview of pathophysiology, models and acute injury mechanisms. Front Neurol 10:282. https:\/\/doi.org\/10.3389\/fneur.2019.00282","journal-title":"Front Neurol"},{"key":"2628_CR2","doi-asserted-by":"publisher","first-page":"1841","DOI":"10.3390\/ijms20081841","volume":"20","author":"E Pinchi","year":"2019","unstructured":"Pinchi E, Frati A, Cantatore S, D\u2019Errico S, La Russa R, Maiese A, Palmieri M, Pesce A, et al (2019) Acute spinal cord injury: a systematic review investigating miRNA families involved. Int J Mol Sci 20:1841. https:\/\/doi.org\/10.3390\/ijms20081841","journal-title":"Int J Mol Sci"},{"key":"2628_CR3","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1016\/j.injury.2018.12.027","volume":"50","author":"Z Hassannejad","year":"2019","unstructured":"Hassannejad Z, Zadegan SA, Vaccaro AR, Rahimi-Movaghar V, Sabzevari O (2019) Biofunctionalized peptide-based hydrogel as an injectable scaffold for BDNF delivery can improve regeneration after spinal cord injury. Injury 50:278\u2013285. https:\/\/doi.org\/10.1016\/j.injury.2018.12.027","journal-title":"Injury"},{"key":"2628_CR4","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.wneu.2013.01.042","volume":"83","author":"BI Awad","year":"2015","unstructured":"Awad BI, Carmody MA, Steinmetz MP (2015) Potential role of growth factors in the management of spinal cord injury. World Neurosurgery 83:120\u2013131. https:\/\/doi.org\/10.1016\/j.wneu.2013.01.042","journal-title":"World Neurosurgery"},{"key":"2628_CR5","doi-asserted-by":"publisher","first-page":"914","DOI":"10.5966\/sctm.2015-0381","volume":"5","author":"CHS Ahuja","year":"2016","unstructured":"Ahuja CHS, Fehlings MG (2016) Concise review: bridging the gap: novel neuroregenerative and neuroprotective strategies in spinal cord injury. Stem Cells Transl Med 5:914\u2013924. https:\/\/doi.org\/10.5966\/sctm.2015-0381","journal-title":"Stem Cells Transl Med"},{"key":"2628_CR6","doi-asserted-by":"publisher","first-page":"9857201","DOI":"10.1155\/2016\/9857201","volume":"2016","author":"SM Garraway","year":"2016","unstructured":"Garraway SM, Huie JR (2016) Spinal plasticity and behavior: BDNF-induced neuromodulation in uninjured and injured spinal cord. Neural Plast 2016:9857201. https:\/\/doi.org\/10.1155\/2016\/9857201","journal-title":"Neural Plast"},{"key":"2628_CR7","doi-asserted-by":"publisher","first-page":"1688","DOI":"10.3892\/etm.2018.7109","volume":"17","author":"J Liang","year":"2019","unstructured":"Liang J, Deng G, Huang H (2019) The activation of BDNF reduced inflammation in a spinal cord injury model by TrkB\/p38 MAPK signaling. Exp Ther Med 17:1688\u20131696. https:\/\/doi.org\/10.3892\/etm.2018.7109","journal-title":"Exp Ther Med"},{"key":"2628_CR8","doi-asserted-by":"publisher","first-page":"3311","DOI":"10.1089\/neu.2017.5175","volume":"34","author":"K Rosich","year":"2017","unstructured":"Rosich K, Hanna BF, Ibrahim RK, Hellenbrand DJ, Hanna A (2017) The effects of glial cell line-derived neurotrophic factor after spinal cord injury. J Neurotrauma 34:3311\u20133325. https:\/\/doi.org\/10.1089\/neu.2017.5175","journal-title":"J Neurotrauma"},{"key":"2628_CR9","doi-asserted-by":"publisher","first-page":"109","DOI":"10.3390\/brainsci8060109","volume":"8","author":"MJ Walker","year":"2018","unstructured":"Walker MJ, Xu XM (2018) History of glial cell line-derived neurotrophic factor (GDNF) and its use for spinal cord injury repair. Brain Sci 8:109. https:\/\/doi.org\/10.3390\/brainsci8060109","journal-title":"Brain Sci"},{"key":"2628_CR10","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.brainres.2008.08.087","volume":"1239","author":"LF Chu","year":"2008","unstructured":"Chu LF, Wang WT, Ghanta VT, Lin CHH, Chiang YY, Hsueh CHM (2008) Ischemic brain cell-derived conditioned medium protects astrocytes against ischemia through GDNF\/ERK\/NF-kB signaling pathway. Brain Res 1239:24\u201335. https:\/\/doi.org\/10.1016\/j.brainres.2008.08.087","journal-title":"Brain Res"},{"key":"2628_CR11","doi-asserted-by":"publisher","unstructured":"Khazaei M, Ahuja CHS, Nakashima H,\u00a0Nagoshi N, Li L, Wang J, Chio J, Badner A, et al (2020) GDNF rescues the fate of neural progenitor grafts by attenuating Notch signals in the injured spinal cord in rodents. Sci Transl Med 12:eaau3538. https:\/\/doi.org\/10.1126\/scitranslmed.aau3538.","DOI":"10.1126\/scitranslmed.aau3538"},{"key":"2628_CR12","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.actbio.2017.07.024","volume":"60","author":"S Liu","year":"2017","unstructured":"Liu S, Sandner B, Schackel T, Nicholson L, Chtarto A, Tenenbaum L, Puttagunta R, M\u00fcller R, et al (2017) Regulated viral BDNF delivery in combination with Schwann cells promotes axonal regeneration through capillary alginate hydrogels after spinal cord injury. Acta Biomater 60:167\u2013180. https:\/\/doi.org\/10.1016\/j.actbio.2017.07.024","journal-title":"Acta Biomater"},{"key":"2628_CR13","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1093\/brain\/awy340","volume":"142","author":"R Eggers","year":"2019","unstructured":"Eggers R, de Winter F, Hoyng SA, Hoeben RC, Malessy MJA, Tannemaat MR, Verhaagen J (2019) Timed GDNF gene therapy using an immune-evasive gene switch promotes long distance axon regeneration. Brain 142:295\u2013311. https:\/\/doi.org\/10.1093\/brain\/awy340","journal-title":"Brain"},{"key":"2628_CR14","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1111\/nyas.12052","volume":"1279","author":"JD Houle","year":"2013","unstructured":"Houle JD, C\u00f4t\u00e9 MP (2013) Axon regeneration and exercise-dependent plasticity after spinal cord injury. Ann N Y Acad Sci 1279:154\u2013163. https:\/\/doi.org\/10.1111\/nyas.12052","journal-title":"Ann N Y Acad Sci"},{"key":"2628_CR15","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.3390\/ijms19041106","volume":"19","author":"K Bimbova","year":"2018","unstructured":"Bimbova K, Bacova M, Kisucka A, Pavel J, Galik J, Zavacky P, Marsala M, Stropkovska A, et al (2018) A single dose of atorvastatin applied acutely after spinal cord injury suppresses inflammation, apoptosis, and promotes axon outgrowth, which might be essential for favorable functional outcome. Int J Mol Sci 19:1106. https:\/\/doi.org\/10.3390\/ijms19041106","journal-title":"Int J Mol Sci"},{"key":"2628_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1089\/neu.1995.12.1","volume":"12","author":"DM Basso","year":"1995","unstructured":"Basso DM, Beattie MS, Bresnahan JC (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12:1\u201321. https:\/\/doi.org\/10.1089\/neu.1995.12.1","journal-title":"J Neurotrauma"},{"key":"2628_CR17","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1016\/j.mcn.2009.05.002","volume":"41","author":"LF Yoong","year":"2009","unstructured":"Yoong LF, Wan G, Too HP (2009) GDNF-induced cell signaling and neurite outgrowths are differentially mediated by GFRalpha1 isoforms. Mol Cell Neurosci 41:464\u2013473. https:\/\/doi.org\/10.1016\/j.mcn.2009.05.002","journal-title":"Mol Cell Neurosci"},{"key":"2628_CR18","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1515\/revneuro-2017-0040","volume":"29","author":"A Nasrolahi","year":"2018","unstructured":"Nasrolahi A, Mahmoudi J, Akbarzadeh A, Karimipour M, Sadigh-Eteghad S, Salehi R, Farhoudi M (2018) Neurotrophic factors hold promise for the future of Parkinson\u2019s disease treatment: is there a light at the end of the tunnel? Rev Neurosci 29:475\u2013489. https:\/\/doi.org\/10.1515\/revneuro-2017-0040","journal-title":"Rev Neurosci"},{"key":"2628_CR19","doi-asserted-by":"publisher","first-page":"792","DOI":"10.4103\/1673-5374.156984","volume":"10","author":"T Liu","year":"2015","unstructured":"Liu T, Cao FJ, Xu DD, Xu JQ, Feng SQ (2015) Upregulated Ras\/Raf\/ERK1\/2 signaling pathway: a new hope in the repair of spinal cord injury. Neural Regen Res 10:792\u2013796. https:\/\/doi.org\/10.4103\/1673-5374.156984","journal-title":"Neural Regen Res"},{"key":"2628_CR20","doi-asserted-by":"publisher","first-page":"6939","DOI":"10.1007\/s12035-018-0885-3","volume":"55","author":"MP Kashyap","year":"2018","unstructured":"Kashyap MP, Roberts C, Waseem M, Tyagi P (2018) Drug targets in neurotrophin signaling in the central and peripheral nervous system. Mol Neurobiol 55:6939\u20136955. https:\/\/doi.org\/10.1007\/s12035-018-0885-3","journal-title":"Mol Neurobiol"},{"key":"2628_CR21","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1007\/s10571-006-9065-5","volume":"26","author":"J Langfort","year":"2006","unstructured":"Langfort J, Bara\u0144czuk E, Pawlak D, Chalimoniuk M, Lukacova N, Marsala J, G\u00f3rski J (2006) The effect of endurance training on regional serotonin metabolism in the brain during early stage of detraining period in the female rat. Cell Mol Neurobiol 26:1327\u20131342. https:\/\/doi.org\/10.1007\/s10571-006-9065-5","journal-title":"Cell Mol Neurobiol"},{"key":"2628_CR22","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.brainres.2015.05.020","volume":"1618","author":"M Chalimoniuk","year":"2015","unstructured":"Chalimoniuk M, Chrapusta SJ, Luk\u00e1\u010dov\u00e1 N, Langfort J (2015) Endurance training upregulates the nitric oxide\/soluble guanylyl cyclase\/cyclic guanosine 3\u2019,5\u2019 monophosphate pathway in the striatum, midbrain and cerebellum of male rats. Brain Res 1618:29\u201340. https:\/\/doi.org\/10.1016\/j.brainres.2015.05.020","journal-title":"Brain Res"},{"key":"2628_CR23","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1093\/ptj\/74.1.50","volume":"74","author":"T Gordon","year":"1994","unstructured":"Gordon T, Mao J (1994) Muscle atrophy and procedures for training after spinal cord injury. Phys Ther 74:50\u201360. https:\/\/doi.org\/10.1093\/ptj\/74.1.50","journal-title":"Phys Ther"},{"key":"2628_CR24","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.expneurol.2017.03.012","volume":"292","author":"K Chen","year":"2017","unstructured":"Chen K, Marsh BC, Cowan M, Al\u2019Joboori, Gigout, Smith, Messenger, Gamper, Schwab, Ichiyama, YZSCCNNMERM (2017) Sequential therapy of anti-Nogo-a antibody treatment and treadmill training leads to cumulative improvements after spinal cord injury in rats. Exp Neurol 292:135\u2013144. https:\/\/doi.org\/10.1016\/j.expneurol.2017.03.012","journal-title":"Exp Neurol"},{"key":"2628_CR25","doi-asserted-by":"publisher","first-page":"335","DOI":"10.12965\/jer.1836264.132","volume":"14","author":"YM Kim","year":"2018","unstructured":"Kim YM, Jin JJ, Lee SJ, Seo TB, Ji ES (2018) Treadmill exercise with bone marrow stromal cells transplantation facilitates neuroprotective effect through BDNF-ERK1\/2 pathway in spinal cord injury rats. J Exerc Rehabil 14:335\u2013340. https:\/\/doi.org\/10.12965\/jer.1836264.132","journal-title":"J Exerc Rehabil"},{"key":"2628_CR26","doi-asserted-by":"publisher","first-page":"1999","DOI":"10.1089\/neu.2019.6961","volume":"37","author":"J Hou","year":"2020","unstructured":"Hou J, Nelson R, Mohammad N, Mustafa G, Plant D, Thompson FJ, Bose P (2020) Effect of simultaneous combined treadmill training and magnetic stimulation on spasticity and gait impairments following cervical spinal cord injury (C-SCI). J Neurotrama 37:1999\u20132013. https:\/\/doi.org\/10.1089\/neu.2019.6961","journal-title":"J Neurotrama"},{"key":"2628_CR27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0032298","volume":"7","author":"F Gomez-Pinilla","year":"2012","unstructured":"Gomez-Pinilla F, Ying Z, Zhuang Y (2012) Brain and spinal cord interaction: protective effects of exercise prior to spinal cord injury. PLoS ONE 7:e32298. https:\/\/doi.org\/10.1371\/journal.pone.0032298","journal-title":"PLoS ONE"},{"key":"2628_CR28","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1007\/s00424-017-1964-4","volume":"469","author":"M Sasi","year":"2017","unstructured":"Sasi M, Vignoli B, Canossa M, Blum R (2017) Neurobiology of local and intercellular BDNF signaling. Eur J Physiol 469:593\u2013610. https:\/\/doi.org\/10.1007\/s00424-017-1964-4","journal-title":"Eur J Physiol"},{"key":"2628_CR29","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1177\/1545968314562110","volume":"29","author":"S Tashiro","year":"2015","unstructured":"Tashiro S, Shinozaki M, Mukaino M, Renault-Mihara F, Toyama Y, Liu M, Nakamura M, Okano H (2015) BDNF induced by treadmill training contributes to the suppression of spasticity and allodynia after spinal cord injury via upregulation of KCC2. Neurorehabil Neural Repair 29:677\u2013689. https:\/\/doi.org\/10.1177\/1545968314562110","journal-title":"Neurorehabil Neural Repair"},{"key":"2628_CR30","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1186\/1471-213X-10-103","volume":"10","author":"C Sciarretta","year":"2010","unstructured":"Sciarretta C, Fritzsch B, Beisel K, Rocha-Sanchez SM, Buniello A, Horn JM, Minichiello L (2010) PLCg-activated signalling is essential for TrkB mediated sensory neuron structural plasticity. BMC Dev Biol 10:103. https:\/\/doi.org\/10.1186\/1471-213X-10-103","journal-title":"BMC Dev Biol"},{"key":"2628_CR31","doi-asserted-by":"publisher","first-page":"2425","DOI":"10.1111\/j.1460-9568.2007.05498.x","volume":"25","author":"M Macias","year":"2007","unstructured":"Macias M, Dwornik A, Ziemlinska E, Fehr S, Schachner M, Czarkowska-Bauch J, Skup M (2007) Locomotor exercise alters expression of pro-brain-derived neurotrophic factor, brain-derived neurotrophic factor and its receptor TrkB in the spinal cord of adult rats. Eur J Neurosci 25:2425\u20132444. https:\/\/doi.org\/10.1111\/j.1460-9568.2007.05498.x","journal-title":"Eur J Neurosci"},{"key":"2628_CR32","doi-asserted-by":"publisher","first-page":"453","DOI":"10.3389\/fncel.2019.00453","volume":"11","author":"T Veremeyko","year":"2019","unstructured":"Veremeyko T, Yung AWY, Dukhinova M, Strekalova T, Ponomarev ED (2019) The role of neuronal factors in the epigenetic reprogramming of microglia in the normal and diseased central nervous system. Front Cell Neurosci 11:453. https:\/\/doi.org\/10.3389\/fncel.2019.00453","journal-title":"Front Cell Neurosci"},{"key":"2628_CR33","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1007\/s12035-014-9035-8","volume":"53","author":"Q Zhang","year":"2016","unstructured":"Zhang Q, Bian G, Chen P, Liu L, Yu C, Liu FF, Xue Q, Chung SK, et al (2016) Aldose reductase regulates microglia\/macrophages polarization through the cAMP response element-binding protein after spinal cord injury in mice. Mol Neurobiol 53:662\u2013676. https:\/\/doi.org\/10.1007\/s12035-014-9035-8","journal-title":"Mol Neurobiol"},{"key":"2628_CR34","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1007\/s12035-018-1135-4","volume":"56","author":"M Mohanraj","year":"2018","unstructured":"Mohanraj M, Sekar P, Liou HH, Chang SF, Lin WW (2018) The mycobacterial adjuvant analogue TDB attenuates neuroinflammation via Mincle-independent PLC-\u03b31\/PKC\/ERK signaling and microglial polarization. Mol Neurobiol 56:1167\u20131187. https:\/\/doi.org\/10.1007\/s12035-018-1135-4","journal-title":"Mol Neurobiol"},{"key":"2628_CR35","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/S0168-0102(03)00095-6","volume":"46","author":"T Morino","year":"2003","unstructured":"Morino T, Ogata T, Horiuchi H, Takeba J, Okumura H, Miyazaki T, Yamamoto H (2003) Delayed neuronal damage related to microglia proliferation after mild spinal cord compression injury. Neurosci Res 46:309\u2013318. https:\/\/doi.org\/10.1016\/S0168-0102(03)00095-6","journal-title":"Neurosci Res"},{"key":"2628_CR36","doi-asserted-by":"publisher","first-page":"2390","DOI":"10.1016\/j.injury.2020.07.007","volume":"51","author":"M Rezvan","year":"2020","unstructured":"Rezvan M, Meknatkhah S, Hassannejad Z, Sharif-Alhoseini M, Zadegan SA, Shokraneh F, Vaccaro AR, Lu Y, et al (2020) Time-dependent microglia and macrophages response after traumatic spinal cord injury in rat: a systematic review. Injury 51:2390\u20132401. https:\/\/doi.org\/10.1016\/j.injury.2020.07.007","journal-title":"Injury"},{"key":"2628_CR37","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1038\/s41467-019-08446-0","volume":"10","author":"V Bellver-Landete","year":"2019","unstructured":"Bellver-Landete V, Bretheau F, Mailhot B, Valli\u00e8res N, Lessard M, Janelle ME, Vernoux N, Tremblay M\u00c8, et al (2019) Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury. Nat Commun 10:518. https:\/\/doi.org\/10.1038\/s41467-019-08446-0","journal-title":"Nat Commun"},{"key":"2628_CR38","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.bbr.2015.04.058","volume":"291","author":"M May","year":"2015","unstructured":"May M, Fouad K, Shum-Siu A, Magnuson DSK (2015) Challenges of animal models in SCI research: effects of pre-injury task-specific training in adult rats before lesion. Behav Brain Res 291:6\u201335. https:\/\/doi.org\/10.1016\/j.bbr.2015.04.058","journal-title":"Behav Brain Res"},{"key":"2628_CR39","doi-asserted-by":"publisher","first-page":"4021","DOI":"10.1016\/j.bmc.2011.05.021","volume":"19","author":"H Lou","year":"2011","unstructured":"Lou H, Fan P, Perez RG, Lou H (2011) Neuroprotective effects of linarin through activation of the PI3K\/Akt pathway in amyloid-b-induced neuronal cell death. Bioorg Med Chem 19:4021\u20134027. https:\/\/doi.org\/10.1016\/j.bmc.2011.05.021","journal-title":"Bioorg Med Chem"},{"key":"2628_CR40","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/S0959-4388(00)00211-7","volume":"11","author":"A Brunet","year":"2001","unstructured":"Brunet A, Datta SR, Greenberg ME (2001) Transcription-dependent and -independent control of neuronal survival by the PI3K\u2013Akt signaling pathway. Curr Opin in Neurobiol 11:297\u2013305. https:\/\/doi.org\/10.1016\/S0959-4388(00)00211-7","journal-title":"Curr Opin in Neurobiol"},{"key":"2628_CR41","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.brainres.2014.10.049","volume":"1619","author":"AR Harvey","year":"2015","unstructured":"Harvey AR, Lovett SJ, Majda BT, Yoon JH, Wheeler LP, Hodgetts SI (2015) Neurotrophic factors for spinal cord repair: which, where, how and when to apply, and for what period of time? Brain Res 1619:36\u201371. https:\/\/doi.org\/10.1016\/j.brainres.2014.10.049","journal-title":"Brain Res"},{"key":"2628_CR42","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.104945","volume":"143","author":"Z Zhong","year":"2020","unstructured":"Zhong Z, Chen A, Fa Z, Ding Z, Xiao L, Wu G, Wang Q, Zhang R (2020) Bone marrow mesenchymal stem cells upregulate PI3K\/AKT pathway and down-regulate NF-\u03baB pathway by secreting glial cell-derived neurotrophic factors to regulate microglial polarization and alleviate deafferentation pain in rats. Neurobiol Dis 143:104945. https:\/\/doi.org\/10.1016\/j.nbd.2020.104945","journal-title":"Neurobiol Dis"},{"key":"2628_CR43","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.118572","volume":"263","author":"H Li","year":"2020","unstructured":"Li H, Kong R, Wan B, Yang L, Zhang S, Cao X, Chen H (2020) Initiation of PI3K\/AKT pathway by IGF-1 decreases spinal cord injury induced endothelial apoptosis and microvascular damage. Life Sci 263:118572. https:\/\/doi.org\/10.1016\/j.lfs.2020.118572","journal-title":"Life Sci"},{"key":"2628_CR44","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1002\/glia.22441","volume":"61","author":"M Domercq","year":"2013","unstructured":"Domercq M, Mato S, Soria FN, Sanchez-Gomez MV, Alberdi E, Matute C (2013) Zn2+-induced ERK activation mediates PARP-1- dependent ischemic-reoxygenation damage to oligodendrocytes. Glia 61:383\u2013393. https:\/\/doi.org\/10.1002\/glia.22441","journal-title":"Glia"},{"key":"2628_CR45","doi-asserted-by":"crossref","first-page":"3879","DOI":"10.3760\/cma.j.issn.0366-6999.20113265","volume":"126","author":"FJ Cao","year":"2013","unstructured":"Cao FJ, Zhang X, Liu T, Li XW, Mazar M, Feng SQ (2013) Up-regulation of Ras\/Raf\/ERK1\/2 signaling in the spinal cord impairs neural cell migration, neurogenesis, synapse formation, and dendritic spine development. Chin Med J 126:3879\u20133885 (PMID: 24157150)","journal-title":"Chin Med J"},{"key":"2628_CR46","doi-asserted-by":"publisher","unstructured":"Xu D, Cao F, Sun S, Liu T, Feng S (2016) Inhibition of the Ras\/Raf\/ERK1\/2 signaling pathway restores cultured spinal cord-injured neuronal migration, adhesion, and dendritic spine development. Neurochem Res 41:2086\u20132096. https:\/\/doi.org\/10.1007\/s11064-016-1921-1","DOI":"10.1007\/s11064-016-1921-1"},{"key":"2628_CR47","doi-asserted-by":"publisher","first-page":"12200","DOI":"10.1074\/jbc.275.16.12200","volume":"275","author":"M Stanciu","year":"2000","unstructured":"Stanciu M, Wang Y, Kentor R, Burke N, Watkins S, Kress G, Reynolds I, Klann E, et al (2000) Persistent activation of ERK contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures. J Biol Chem 275:12200\u201312206. https:\/\/doi.org\/10.1074\/jbc.275.16.12200","journal-title":"J Biol Chem"},{"key":"2628_CR48","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.expneurol.2006.01.003","volume":"199","author":"ED Crown","year":"2006","unstructured":"Crown ED, Ye Z, Johnson KM, Xu GY, McAdoo DJ, Hulsebosch CE (2006) Increases in the activated forms of ERK 1\/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury. Exp Neurol 199:397\u2013407. https:\/\/doi.org\/10.1016\/j.expneurol.2006.01.003","journal-title":"Exp Neurol"},{"key":"2628_CR49","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2020.113251","volume":"328","author":"M Matsuda","year":"2020","unstructured":"Matsuda M, Kanno H, Sugaya T, Yamaya S, Yahata K, Handa K, Shindo T, Shimokawa H, et al (2020) Low-energy extracorporeal shock wave therapy promotes BDNF expression and improves functional recovery after spinal cord injury in rats. Exp Neurol 328:113251. https:\/\/doi.org\/10.1016\/j.expneurol.2020.113251","journal-title":"Exp Neurol"},{"key":"2628_CR50","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1113\/expphysiol.2009.048561","volume":"94","author":"BK Pedersen","year":"2009","unstructured":"Pedersen BK, Pedersen M, Krabbe KS, Bruunsgaard H, Matthews VB, Febbraio MA (2009) Role of exercise-induced brain-derived neurotrophic factor production in the regulation of energy homeostasis in mammals. Exp Physiol 94:1153\u20131160. https:\/\/doi.org\/10.1113\/expphysiol.2009.048561","journal-title":"Exp Physiol"},{"key":"2628_CR51","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1089\/neu.2010.1594","volume":"28","author":"MP C\u00f4t\u00e9","year":"2011","unstructured":"C\u00f4t\u00e9 MP, Azzam GA, Lemay MA, Zhukareva V, Houl\u00e9 JD (2011) Activity-dependent increase in neurotrophic factors is associated with an enhanced modulation of spinal reflexes after spinal cord injury. J Neurotrauma 28:299\u2013309. https:\/\/doi.org\/10.1089\/neu.2010.1594","journal-title":"J Neurotrauma"}],"container-title":["Molecular Neurobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-021-02628-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12035-021-02628-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-021-02628-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,12]],"date-time":"2024-09-12T17:07:01Z","timestamp":1726160821000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12035-021-02628-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,22]]},"references-count":51,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["2628"],"URL":"https:\/\/doi.org\/10.1007\/s12035-021-02628-y","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-693252\/v1","asserted-by":"object"}]},"ISSN":["0893-7648","1559-1182"],"issn-type":[{"value":"0893-7648","type":"print"},{"value":"1559-1182","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,22]]},"assertion":[{"value":"8 July 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 October 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 November 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"We hereby state that this is an original study presenting novel results. The manuscript has not been previously published in any language anywhere and it is not under simultaneous consideration or in press with another journal.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"\u2018Not applicable\u2019 for this section.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"\u2018Not applicable\u2019 for this section.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}