{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:36:21Z","timestamp":1792787781738,"version":"4.5.0"},"reference-count":84,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":80,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Consejo Superior de Investigaciones Cientificas","id":[{"id":"https:\/\/ror.org\/02gfc7t72","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Noise-induced hearing loss (NIHL) is the second leading cause of deafness globally. However, effective pharmacological treatments remain unavailable. Excitotoxicity, an early NIHL event, is a central mechanism in degeneration of cochlear synapses established between inner hair cells (IHCs) and spiral ganglion neurons (SGNs). This excitotoxic damage can trigger the degradation of the neurotrophic TrkB receptor, thereby inhibiting brain-derived neurotrophic factor (BDNF) signaling and challenging neurotrophin-based therapies for hearing loss.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed an ex vivo model of excitotoxicity, where excitotoxicity was induced in cochlear explants by overstimulation of excitatory glutamate receptors, and an in vivo model of noise overexposure. The effects of excitotoxicity on the neurotrophic system and cell architecture were established by immunohistochemistry. Hearing function was evaluated in vivo by the auditory brainstem responses (ABR) test, performed before and after noise overexposure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In this study, we evaluated the therapeutic potential in the inner ear of MTFL\n                      <jats:sub>457<\/jats:sub>\n                      , a cell-penetrating peptide designed to prevent TrkB-FL degradation in brain excitotoxicity. MTFL\n                      <jats:sub>457<\/jats:sub>\n                      showed efficient distribution across cochlear cell types in both ex vivo and in vivo models, supporting its ability to reach the inner ear and suggesting that it can cross the blood-labyrinth barrier after systemic administration. In explants undergoing excitotoxicity, MTFL\n                      <jats:sub>457<\/jats:sub>\n                      prevented TrkB-FL dysregulation, partially restored downstream prosurvival signaling, and significantly reduced neuronal damage and features associated with cochlear synaptopathy. In vivo, despite known sex-dependent differences in susceptibility to noise-induced damage, treatment with MTFL\n                      <jats:sub>457<\/jats:sub>\n                      preserved auditory function and synaptic integrity in both males and females, although the magnitude of protection varied between sexes. Together, these findings support a protective effect of MTFL\n                      <jats:sub>457<\/jats:sub>\n                      in models of excitotoxic cochlear injury.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These results support the therapeutic potential of peptide MTFL\n                      <jats:sub>457<\/jats:sub>\n                      for treatment of NIHL and possibly other types of sensorineural hearing loss likewise associated with excitotoxicity.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s10020-026-01539-9","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T01:16:54Z","timestamp":1782695814000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Neuroprotective potential of a TrkB-FL-derived cell-penetrating peptide in cochlear synaptopathy and noise-induced hearing loss"],"prefix":"10.1186","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8171-7828","authenticated-orcid":false,"given":"Elena","family":"Torres-Campos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3077-0500","authenticated-orcid":false,"given":"Isabel","family":"Varela-Nieto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4478-0956","authenticated-orcid":false,"given":"Margarita","family":"D\u00edaz-Guerra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"issue":"14","key":"1539_CR1","doi-asserted-by":"publisher","first-page":"6746","DOI":"10.7150\/thno.60701","volume":"11","author":"S Ayuso-Dolado","year":"2021","unstructured":"Ayuso-Dolado S, Esteban-Ortega GM, Vidaurre OG, Diaz-Guerra M. A novel cell-penetrating peptide targeting calpain-cleavage of PSD-95 induced by excitotoxicity improves neurological outcome after stroke. Theranostics. 2021;11(14):6746\u201365.","journal-title":"Theranostics"},{"issue":"12","key":"1539_CR2","doi-asserted-by":"publisher","first-page":"e13275","DOI":"10.1111\/acel.13275","volume":"19","author":"JM Bermudez-Munoz","year":"2020","unstructured":"Bermudez-Munoz JM, Celaya AM, Hijazo-Pechero S, Wang J, Serrano M, Varela-Nieto I. G6PD overexpression protects from oxidative stress and age-related hearing loss. Aging Cell. 2020;19(12):e13275.","journal-title":"Aging Cell"},{"issue":"5443","key":"1539_CR3","doi-asserted-by":"publisher","first-page":"1358","DOI":"10.1126\/science.286.5443.1358","volume":"286","author":"A Bonni","year":"1999","unstructured":"Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science. 1999;286(5443):1358\u201362.","journal-title":"Science"},{"issue":"2","key":"1539_CR4","doi-asserted-by":"publisher","first-page":"e1001478","DOI":"10.1371\/journal.pbio.1001478","volume":"11","author":"C Cao","year":"2013","unstructured":"Cao C, Rioult-Pedotti MS, Migani P, Yu CJ, Tiwari R, Parang K, et al. Impairment of TrkB-PSD-95 signaling in Angelman syndrome. PLoS Biol. 2013;11(2):e1001478.","journal-title":"PLoS Biol"},{"key":"1539_CR5","doi-asserted-by":"publisher","first-page":"103706","DOI":"10.1016\/j.mcn.2022.103706","volume":"120","author":"GA Caprara","year":"2022","unstructured":"Caprara GA, Peng AW. Mechanotransduction in mammalian sensory hair cells. Mol Cell Neurosci. 2022;120:103706.","journal-title":"Mol Cell Neurosci"},{"issue":"2","key":"1539_CR6","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1111\/j.1460-9568.2005.04584.x","volume":"23","author":"R Cediel","year":"2006","unstructured":"Cediel R, Riquelme R, Contreras J, Diaz A, Varela-Nieto I. Sensorineural hearing loss in insulin-like growth factor I-null mice: a new model of human deafness. Eur J Neurosci. 2006;23(2):587\u201390.","journal-title":"Eur J Neurosci"},{"issue":"4","key":"1539_CR7","doi-asserted-by":"publisher","first-page":"242","DOI":"10.2471\/BLT.21.285643","volume":"99","author":"S Chadha","year":"2021","unstructured":"Chadha S, Kamenov K, Cieza A. The world report on hearing, 2021. Bull World Health Organ. 2021;99(4):242\u2013A242.","journal-title":"Bull World Health Organ"},{"issue":"39","key":"1539_CR8","doi-asserted-by":"publisher","first-page":"27467","DOI":"10.1074\/jbc.274.39.27467","volume":"274","author":"KS Christopherson","year":"1999","unstructured":"Christopherson KS, Hillier BJ, Lim WA, Bredt DS. PSD-95 assembles a ternary complex with the N-methyl-D-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain. J Biol Chem. 1999;274(39):27467\u201373.","journal-title":"J Biol Chem"},{"issue":"5","key":"1539_CR9","doi-asserted-by":"publisher","first-page":"e22087","DOI":"10.1002\/syn.22087","volume":"73","author":"TM Coate","year":"2019","unstructured":"Coate TM, Scott MK, Gurjar M. Current concepts in cochlear ribbon synapse formation. Synapse. 2019;73(5):e22087.","journal-title":"Synapse"},{"issue":"8","key":"1539_CR10","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1016\/j.apacoust.2009.03.005","volume":"70","author":"P Cobo","year":"2009","unstructured":"Cobo P, Murillo-Cuesta S, Cediel R, Moreno A, Lorenzo-Garc\u00eda P, Varela-Nieto I. Design of a reverberant chamber for noise exposure experiments with small animals. Appl Acoust. 2009;70(8):1034\u201340.","journal-title":"Appl Acoust"},{"issue":"2","key":"1539_CR11","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1056\/NEJMcibr1413201","volume":"372","author":"LL Cunningham","year":"2015","unstructured":"Cunningham LL, Tucci DL. Restoring synaptic connections in the inner ear after noise damage. N Engl J Med. 2015;372(2):181\u20132.","journal-title":"N Engl J Med"},{"issue":"4","key":"1539_CR12","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1002\/syn.1048","volume":"40","author":"C Davies","year":"2001","unstructured":"Davies C, Tingley D, Kachar B, Wenthold RJ, Petralia RS. Distribution of members of the PSD-95 family of MAGUK proteins at the synaptic region of inner and outer hair cells of the guinea pig cochlea. Synapse. 2001;40(4):258\u201368.","journal-title":"Synapse"},{"issue":"3","key":"1539_CR13","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/j.trci.2017.06.003","volume":"3","author":"JA Deal","year":"2017","unstructured":"Deal JA, Albert MS, Arnold M, Bangdiwala SI, Chisolm T, Davis S, et al. A randomized feasibility pilot trial of hearing treatment for reducing cognitive decline: results from the aging and cognitive health evaluation in elders pilot study. Alzheimers Dement (N Y). 2017;3(3):410\u20135.","journal-title":"Alzheimers Dement (N Y)"},{"issue":"3","key":"1539_CR14","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1016\/j.mcn.2004.03.007","volume":"26","author":"R Deogracias","year":"2004","unstructured":"Deogracias R, Espliguero G, Iglesias T, Rodriguez-Pena A. Expression of the neurotrophin receptor trkB is regulated by the cAMP\/CREB pathway in neurons. Mol Cell Neurosci. 2004;26(3):470\u201380.","journal-title":"Mol Cell Neurosci"},{"issue":"1","key":"1539_CR15","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1038\/s41419-025-07990-6","volume":"16","author":"GM Esteban-Ortega","year":"2025","unstructured":"Esteban-Ortega GM, Torres-Campos E, Diaz-Guerra M. Retrograde transport of neurotrophin receptor TrkB-FL induced by excitotoxicity regulates Golgi stability and is a target for stroke neuroprotection. Cell Death Dis. 2025;16(1):659.","journal-title":"Cell Death Dis"},{"issue":"6","key":"1539_CR16","doi-asserted-by":"publisher","first-page":"3937","DOI":"10.1121\/10.0011510","volume":"151","author":"AC Foster","year":"2022","unstructured":"Foster AC, Szobota S, Piu F, Jacques BE, Moore DR, Sanchez VA, Anderson JJ. A neurotrophic approach to treating hearing loss: Translation from animal models to clinical proof-of-concept. J Acoust Soc Am. 2022;151(6):3937.","journal-title":"J Acoust Soc Am"},{"issue":"2","key":"1539_CR17","first-page":"657","volume":"15","author":"LM Frago","year":"2000","unstructured":"Frago LM, Camerero G, Canon S, Paneda C, Sanz C, Leon Y, et al. Role of diffusible and transcription factors in inner ear development: implications in regeneration. Histol Histopathol. 2000;15(2):657\u201366.","journal-title":"Histol Histopathol"},{"issue":"2","key":"1539_CR18","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1038\/nn796","volume":"5","author":"E Glowatzki","year":"2002","unstructured":"Glowatzki E, Fuchs PA. Transmitter release at the hair cell ribbon synapse. Nat Neurosci. 2002;5(2):147\u201354.","journal-title":"Nat Neurosci"},{"issue":"4","key":"1539_CR19","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.conb.2008.09.006","volume":"18","author":"E Glowatzki","year":"2008","unstructured":"Glowatzki E, Grant L, Fuchs P. Hair cell afferent synapses. Curr Opin Neurobiol. 2008;18(4):389\u201395.","journal-title":"Curr Opin Neurobiol"},{"issue":"1\u20132","key":"1539_CR20","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.jns.2006.01.019","volume":"246","author":"NK Gonatas","year":"2006","unstructured":"Gonatas NK, Stieber A, Gonatas JO. Fragmentation of the Golgi apparatus in neurodegenerative diseases and cell death. J Neurol Sci. 2006;246(1\u20132):21\u201330.","journal-title":"J Neurol Sci"},{"issue":"11","key":"1539_CR21","doi-asserted-by":"publisher","first-page":"1877","DOI":"10.1002\/ar.22587","volume":"295","author":"SH Green","year":"2012","unstructured":"Green SH, Bailey E, Wang Q, Davis RL, The Trk A. C\u2019s of neurotrophins in the cochlea. Anat Rec (Hoboken). 2012;295(11):1877\u201395.","journal-title":"Anat Rec (Hoboken)"},{"issue":"23","key":"1539_CR22","doi-asserted-by":"publisher","first-page":"8750","DOI":"10.1523\/JNEUROSCI.20-23-08750.2000","volume":"20","author":"N Hakuba","year":"2000","unstructured":"Hakuba N, Koga K, Gyo K, Usami SI, Tanaka K. Exacerbation of noise-induced hearing loss in mice lacking the glutamate transporter GLAST. J Neurosci. 2000;20(23):8750\u20133.","journal-title":"J Neurosci"},{"issue":"7","key":"1539_CR23","doi-asserted-by":"publisher","first-page":"3828","DOI":"10.1073\/pnas.1914247117","volume":"117","author":"N Hu","year":"2020","unstructured":"Hu N, Rutherford MA, Green SH. Protection of cochlear synapses from noise-induced excitotoxic trauma by blockade of Ca(2+)-permeable AMPA receptors. Proc Natl Acad Sci U S A. 2020;117(7):3828\u201338.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1\u20132","key":"1539_CR24","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/0378-5955(89)90100-7","volume":"40","author":"JM Juiz","year":"1989","unstructured":"Juiz JM, Rueda J, Merchan JA, Sala ML. The effects of kainic acid on the cochlear ganglion of the rat. Hear Res. 1989;40(1\u20132):65\u201374.","journal-title":"Hear Res"},{"key":"1539_CR25","doi-asserted-by":"publisher","first-page":"666706","DOI":"10.3389\/fncel.2021.666706","volume":"15","author":"JS Kempfle","year":"2021","unstructured":"Kempfle JS, Duro MV, Zhang A, Amador CD, Kuang R, Lu R, et al. A novel small molecule neurotrophin-3 analogue promotes inner ear neurite outgrowth and synaptogenesis in vitro. Front Cell Neurosci. 2021;15:666706.","journal-title":"Front Cell Neurosci"},{"issue":"23","key":"1539_CR26","doi-asserted-by":"publisher","first-page":"4434","DOI":"10.1523\/JNEUROSCI.2228-18.2019","volume":"39","author":"KX Kim","year":"2019","unstructured":"Kim KX, Payne S, Yang-Hood A, Li SZ, Davis B, Carlquist J, et al. Vesicular glutamatergic transmission in noise-induced loss and repair of cochlear ribbon synapses. J Neurosci. 2019;39(23):4434\u201347.","journal-title":"J Neurosci"},{"issue":"12","key":"1539_CR27","doi-asserted-by":"publisher","first-page":"13734","DOI":"10.1096\/fj.201901543R","volume":"33","author":"L Klotz","year":"2019","unstructured":"Klotz L, Wendler O, Frischknecht R, Shigemoto R, Schulze H, Enz R. Localization of group II and III metabotropic glutamate receptors at pre- and postsynaptic sites of inner hair cell ribbon synapses. FASEB J. 2019;33(12):13734\u201346.","journal-title":"FASEB J"},{"issue":"45","key":"1539_CR28","doi-asserted-by":"publisher","first-page":"14077","DOI":"10.1523\/JNEUROSCI.2845-09.2009","volume":"29","author":"SG Kujawa","year":"2009","unstructured":"Kujawa SG, Liberman MC. Adding insult to injury: cochlear nerve degeneration after temporary noise-induced hearing loss. J Neurosci. 2009;29(45):14077\u201385.","journal-title":"J Neurosci"},{"issue":"Pt B","key":"1539_CR29","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.heares.2015.02.009","volume":"330","author":"SG Kujawa","year":"2015","unstructured":"Kujawa SG, Liberman MC. Synaptopathy in the noise-exposed and aging cochlea: Primary neural degeneration in acquired sensorineural hearing loss. Hear Res. 2015;330(Pt B):191\u20139.","journal-title":"Hear Res"},{"key":"1539_CR30","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.heares.2016.11.013","volume":"349","author":"A Kurabi","year":"2017","unstructured":"Kurabi A, Keithley EM, Housley GD, Ryan AF, Wong AC. Cellular mechanisms of noise-induced hearing loss. Hear Res. 2017;349:129\u201337.","journal-title":"Hear Res"},{"issue":"11","key":"1539_CR31","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1080\/17425247.2019.1665021","volume":"16","author":"K Kurrikoff","year":"2019","unstructured":"Kurrikoff K, Langel U. Recent CPP-based applications in medicine. Expert Opin Drug Deliv. 2019;16(11):1183\u201391.","journal-title":"Expert Opin Drug Deliv"},{"issue":"1","key":"1539_CR32","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/s40463-017-0219-x","volume":"46","author":"TN Le","year":"2017","unstructured":"Le TN, Straatman LV, Lea J, Westerberg B. Current insights in noise-induced hearing loss: a literature review of the underlying mechanism, pathophysiology, asymmetry, and management options. J Otolaryngol Head Neck Surg. 2017;46(1):41.","journal-title":"J Otolaryngol Head Neck Surg"},{"issue":"13","key":"1539_CR33","doi-asserted-by":"publisher","first-page":"4599","DOI":"10.1523\/JNEUROSCI.4923-13.2014","volume":"34","author":"MC Liberman","year":"2014","unstructured":"Liberman MC, Liberman LD, Maison SF. Efferent feedback slows cochlear aging. J Neurosci. 2014;34(13):4599\u2013607.","journal-title":"J Neurosci"},{"issue":"3","key":"1539_CR34","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1007\/s00420-015-1083-5","volume":"89","author":"A Lie","year":"2016","unstructured":"Lie A, Skogstad M, Johannessen HA, Tynes T, Mehlum IS, Nordby KC, et al. Occupational noise exposure and hearing: a systematic review. Int Arch Occup Environ Health. 2016;89(3):351\u201372.","journal-title":"Int Arch Occup Environ Health"},{"issue":"8","key":"1539_CR36","doi-asserted-by":"publisher","first-page":"e237","DOI":"10.1097\/MAO.0000000000001408","volume":"38","author":"VYW Lin","year":"2017","unstructured":"Lin VYW, Black SE. Linking deafness and dementia: challenges and opportunities. Otol Neurotol. 2017;38(8):e237\u20139.","journal-title":"Otol Neurotol"},{"key":"1539_CR35","doi-asserted-by":"publisher","first-page":"108271","DOI":"10.1016\/j.heares.2021.108271","volume":"419","author":"N Lin","year":"2022","unstructured":"Lin N, Urata S, Cook R, Makishima T. Sex differences in the auditory functions of rodents. Hear Res. 2022;419:108271.","journal-title":"Hear Res"},{"issue":"14","key":"1539_CR37","doi-asserted-by":"publisher","first-page":"8532","DOI":"10.1073\/pnas.1332804100","volume":"100","author":"L Liu","year":"2003","unstructured":"Liu L, Cavanaugh JE, Wang Y, Sakagami H, Mao Z, Xia Z. ERK5 activation of MEF2-mediated gene expression plays a critical role in BDNF-promoted survival of developing but not mature cortical neurons. Proc Natl Acad Sci U S A. 2003;100(14):8532\u20137.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1539_CR38","doi-asserted-by":"crossref","unstructured":"Ma Y, Wise AK, Shepherd RK, Richardson RT. New molecular therapies for the treatment of hearing loss. Pharmacol Ther. 2019; 200: 190\u2013209.","DOI":"10.1016\/j.pharmthera.2019.05.003"},{"issue":"7","key":"1539_CR39","doi-asserted-by":"publisher","first-page":"748","DOI":"10.3390\/cells8070748","volume":"8","author":"JA Martinez-Menarguez","year":"2019","unstructured":"Martinez-Menarguez JA, Tomas M, Martinez-Martinez N, Martinez-Alonso E. Golgi fragmentation in neurodegenerative diseases: is there a common cause? Cells. 2019;8(7):748.","journal-title":"Cells"},{"issue":"121","key":"1539_CR40","doi-asserted-by":"publisher","first-page":"59","DOI":"10.4103\/nah.nah_124_23","volume":"26","author":"A Mehrotra","year":"2024","unstructured":"Mehrotra A, Shukla SP, Shukla AK, Manar MK, Singh SK, Mehrotra M. A comprehensive review of auditory and non-auditory effects of noise on human health. Noise Health. 2024;26(121):59\u201369.","journal-title":"Noise Health"},{"issue":"4","key":"1539_CR41","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1016\/j.neuroscience.2009.11.025","volume":"165","author":"I Meltser","year":"2010","unstructured":"Meltser I, Tahera Y, Canlon B. Differential activation of mitogen-activated protein kinases and brain-derived neurotrophic factor after temporary or permanent damage to a sensory system. Neuroscience. 2010;165(4):1439\u201346.","journal-title":"Neuroscience"},{"issue":"1","key":"1539_CR42","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s13293-018-0171-0","volume":"9","author":"B Milon","year":"2018","unstructured":"Milon B, Mitra S, Song Y, Margulies Z, Casserly R, Drake V, et al. The impact of biological sex on the response to noise and otoprotective therapies against acoustic injury in mice. Biol Sex Differ. 2018;9(1):12.","journal-title":"Biol Sex Differ"},{"issue":"107","key":"1539_CR43","first-page":"53561","volume":"1","author":"SC Montgomery","year":"2016","unstructured":"Montgomery SC, Cox BC. Whole mount dissection and immunofluorescence of the adult mouse cochlea. J Vis Exp. 2016;1(107):53561.","journal-title":"J Vis Exp"},{"issue":"1","key":"1539_CR44","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1186\/s12974-025-03561-w","volume":"22","author":"S Murillo-Cuesta","year":"2025","unstructured":"Murillo-Cuesta S, Seoane E, Cervantes B, Zubeldia JM, Varela-Nieto I. NLRP3 inflammasome and hearing loss: from mechanisms to therapies. J Neuroinflammation. 2025;22(1):225.","journal-title":"J Neuroinflammation"},{"issue":"6","key":"1539_CR45","doi-asserted-by":"publisher","first-page":"2347","DOI":"10.3390\/jcm12062347","volume":"12","author":"N Natarajan","year":"2023","unstructured":"Natarajan N, Batts S, Stankovic KM. Noise-induced hearing loss. J Clin Med. 2023;12(6):2347.","journal-title":"J Clin Med"},{"key":"1539_CR46","doi-asserted-by":"publisher","first-page":"121814","DOI":"10.1016\/j.lfs.2023.121814","volume":"328","author":"D Neves","year":"2023","unstructured":"Neves D, Salazar IL, Almeida RD, Silva RM. Molecular mechanisms of ischemia and glutamate excitotoxicity. Life Sci. 2023;328:121814.","journal-title":"Life Sci"},{"issue":"Pt 2","key":"1539_CR47","doi-asserted-by":"publisher","first-page":"2338","DOI":"10.1523\/JNEUROSCI.15-03-02338.1995","volume":"15","author":"AS Niedzielski","year":"1995","unstructured":"Niedzielski AS, Wenthold RJ. Expression of AMPA, kainate, and NMDA receptor subunits in cochlear and vestibular ganglia. J Neurosci. 1995;15(Pt 2):2338\u201353.","journal-title":"J Neurosci"},{"issue":"482","key":"1539_CR48","doi-asserted-by":"publisher","first-page":"eaao0935","DOI":"10.1126\/scitranslmed.aao0935","volume":"11","author":"S Nyberg","year":"2019","unstructured":"Nyberg S, Abbott NJ, Shi X, Steyger PS, Dabdoub A. Delivery of therapeutics to the inner ear: The challenge of the blood-labyrinth barrier. Sci Transl Med. 2019;11(482):eaao0935.","journal-title":"Sci Transl Med"},{"key":"1539_CR49","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.coph.2020.12.006","volume":"56","author":"J Pagano","year":"2021","unstructured":"Pagano J, Giona F, Beretta S, Verpelli C, Sala C. N-methyl-D-aspartate receptor function in neuronal and synaptic development and signaling. Curr Opin Pharmacol. 2021;56:93\u2013101.","journal-title":"Curr Opin Pharmacol"},{"issue":"5","key":"1539_CR50","doi-asserted-by":"publisher","first-page":"5942","DOI":"10.1096\/fj.201801533R","volume":"33","author":"T Partearroyo","year":"2019","unstructured":"Partearroyo T, Murillo-Cuesta S, Vallecillo N, Bermudez-Munoz JM, Rodriguez-de la Rosa L, Mandruzzato G, et al. Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated with plasma hyperhomocysteinemia. FASEB J. 2019;33(5):5942\u201356.","journal-title":"FASEB J"},{"issue":"5","key":"1539_CR51","doi-asserted-by":"publisher","first-page":"2097","DOI":"10.1021\/acs.molpharmaceut.3c01167","volume":"21","author":"M Pirhaghi","year":"2024","unstructured":"Pirhaghi M, Mamashli F, Moosavi-Movahedi F, Arghavani P, Amiri A, Davaeil B, et al. Cell-penetrating peptides: promising therapeutics and drug-delivery systems for neurodegenerative diseases. Mol Pharm. 2024;21(5):2097\u2013117.","journal-title":"Mol Pharm"},{"key":"1539_CR52","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/S0070-2153(03)57007-7","volume":"57","author":"U Pirvola","year":"2003","unstructured":"Pirvola U, Ylikoski J. Neurotrophic factors during inner ear development. Curr Top Dev Biol. 2003;57:207\u201323.","journal-title":"Curr Top Dev Biol"},{"issue":"1","key":"1539_CR53","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/0306-4522(91)90103-U","volume":"45","author":"JL Puel","year":"1991","unstructured":"Puel JL, Pujol R, Ladrech S, Eybalin M. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid electrophysiological and neurotoxic effects in the guinea-pig cochlea. Neuroscience. 1991;45(1):63\u201372.","journal-title":"Neuroscience"},{"issue":"2","key":"1539_CR54","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1002\/cne.903410209","volume":"341","author":"JL Puel","year":"1994","unstructured":"Puel JL, Pujol R, Tribillac F, Ladrech S, Eybalin M. Excitatory amino acid antagonists protect cochlear auditory neurons from excitotoxicity. J Comp Neurol. 1994;341(2):241\u201356.","journal-title":"J Comp Neurol"},{"issue":"9","key":"1539_CR55","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.1097\/00001756-199806220-00037","volume":"9","author":"JL Puel","year":"1998","unstructured":"Puel JL, Ruel J, Gervais d\u2019Aldin C, Pujol R. Excitotoxicity and repair of cochlear synapses after noise-trauma induced hearing loss. NeuroReport. 1998;9(9):2109\u201314.","journal-title":"NeuroReport"},{"issue":"2","key":"1539_CR56","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/0378-5955(85)90006-1","volume":"18","author":"R Pujol","year":"1985","unstructured":"Pujol R, Lenoir M, Robertson D, Eybalin M, Johnstone BM. Kainic acid selectively alters auditory dendrites connected with cochlear inner hair cells. Hear Res. 1985;18(2):145\u201351.","journal-title":"Hear Res"},{"issue":"1473","key":"1539_CR57","doi-asserted-by":"publisher","first-page":"1545","DOI":"10.1098\/rstb.2006.1894","volume":"361","author":"LF Reichardt","year":"2006","unstructured":"Reichardt LF. Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci. 2006;361(1473):1545\u201364.","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"issue":"2","key":"1539_CR58","doi-asserted-by":"publisher","first-page":"149","DOI":"10.3390\/antiox13020149","volume":"13","author":"AR Saidia","year":"2024","unstructured":"Saidia AR, Francois F, Casas F, Mechaly I, Venteo S, Veechi JT, et al. Oxidative stress plays an important role in glutamatergic excitotoxicity-induced cochlear synaptopathy: implication for therapeutic molecules screening. Antioxid (Basel). 2024;13(2):149.","journal-title":"Antioxid (Basel)"},{"key":"1539_CR59","first-page":"7","volume":"7","author":"L Sanz","year":"2015","unstructured":"Sanz L, Murillo-Cuesta S, Cobo P, Cediel-Algovia R, Contreras J, Rivera T, et al. Swept-sine noise-induced damage as a hearing loss model for preclinical assays. Front Aging Neurosci. 2015;7:7.","journal-title":"Front Aging Neurosci"},{"issue":"7","key":"1539_CR60","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","volume":"9","author":"J Schindelin","year":"2012","unstructured":"Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9(7):676\u201382.","journal-title":"Nat Methods"},{"issue":"34","key":"1539_CR61","doi-asserted-by":"publisher","first-page":"13686","DOI":"10.1523\/JNEUROSCI.1783-13.2013","volume":"33","author":"Y Sergeyenko","year":"2013","unstructured":"Sergeyenko Y, Lall K, Liberman MC, Kujawa SG. Age-related cochlear synaptopathy: an early-onset contributor to auditory functional decline. J Neurosci. 2013;33(34):13686\u201394.","journal-title":"J Neurosci"},{"issue":"6","key":"1539_CR62","doi-asserted-by":"publisher","first-page":"3656","DOI":"10.1121\/1.5111870","volume":"145","author":"BZ Shuster","year":"2019","unstructured":"Shuster BZ, Depireux DA, Mong JA, Hertzano R. Sex differences in hearing: probing the role of estrogen signaling. J Acoust Soc Am. 2019;145(6):3656.","journal-title":"J Acoust Soc Am"},{"issue":"5","key":"1539_CR63","doi-asserted-by":"publisher","first-page":"e12940","DOI":"10.1111\/nan.12940","volume":"49","author":"A Skupien-Jaroszek","year":"2023","unstructured":"Skupien-Jaroszek A, Szczepankiewicz AA, Rysz A, Marchel A, Matyja E, Grajkowska W, et al. Morphological alterations of the neuronal Golgi apparatus upon seizures. Neuropathol Appl Neurobiol. 2023;49(5):e12940.","journal-title":"Neuropathol Appl Neurobiol"},{"issue":"9","key":"1539_CR64","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1097\/MAO.0000000000001191","volume":"37","author":"DJ Sly","year":"2016","unstructured":"Sly DJ, Campbell L, Uschakov A, Saief ST, Lam M, O\u2019Leary SJ. Applying neurotrophins to the round window rescues auditory function and reduces inner hair cell synaptopathy after noise-induced hearing loss. Otol Neurotol. 2016;37(9):1223\u201330.","journal-title":"Otol Neurotol"},{"issue":"5","key":"1539_CR65","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1097\/MAO.0000000000002229","volume":"40","author":"H Staecker","year":"2019","unstructured":"Staecker H, Jokovic G, Karpishchenko S, Kienle-Gogolok A, Krzyzaniak A, Lin CD, et al. Efficacy and safety of AM-111 in the treatment of acute unilateral sudden deafness-a double-blind, randomized, placebo-controlled phase 3 study. Otol Neurotol. 2019;40(5):584\u201394.","journal-title":"Otol Neurotol"},{"issue":"1","key":"1539_CR66","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1002\/cne.21227","volume":"501","author":"M Sugawara","year":"2007","unstructured":"Sugawara M, Murtie JC, Stankovic KM, Liberman MC, Corfas G. Dynamic patterns of neurotrophin 3 expression in the postnatal mouse inner ear. J Comp Neurol. 2007;501(1):30\u20137.","journal-title":"J Comp Neurol"},{"key":"1539_CR67","doi-asserted-by":"publisher","first-page":"24907","DOI":"10.1038\/srep24907","volume":"6","author":"J Suzuki","year":"2016","unstructured":"Suzuki J, Corfas G, Liberman MC. Round-window delivery of neurotrophin 3 regenerates cochlear synapses after acoustic overexposure. Sci Rep. 2016;6:24907.","journal-title":"Sci Rep"},{"issue":"1","key":"1539_CR68","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1080\/00016489.2017.1367100","volume":"138","author":"A Szibor","year":"2018","unstructured":"Szibor A, Hyvarinen P, Lehtimaki J, Pirvola U, Ylikoski M, Makitie A, et al. Hearing disorder from music; a neglected dysfunction. Acta Otolaryngol. 2018;138(1):21\u20134.","journal-title":"Acta Otolaryngol"},{"issue":"10","key":"1539_CR69","doi-asserted-by":"publisher","first-page":"e0224022","DOI":"10.1371\/journal.pone.0224022","volume":"14","author":"S Szobota","year":"2019","unstructured":"Szobota S, Mathur PD, Siegel S, Black K, Saragovi HU, Foster AC, BDNF. NT-3 and Trk receptor agonist monoclonal antibodies promote neuron survival, neurite extension, and synapse restoration in rat cochlea ex vivo models relevant for hidden hearing loss. PLoS ONE. 2019;14(10):e0224022.","journal-title":"PLoS ONE"},{"issue":"4","key":"1539_CR70","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/S0896-6273(00)81010-7","volume":"20","author":"X Tao","year":"1998","unstructured":"Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME. Ca2\u2009+\u2009influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron. 1998;20(4):709\u201326.","journal-title":"Neuron"},{"issue":"2","key":"1539_CR72","doi-asserted-by":"publisher","first-page":"268","DOI":"10.3390\/ijms18020268","volume":"18","author":"GS Tejeda","year":"2017","unstructured":"Tejeda GS, Diaz-Guerra M. Integral characterization of defective BDNF\/TrkB signalling in neurological and psychiatric disorders leads the way to new therapies. Int J Mol Sci. 2017;18(2):268.","journal-title":"Int J Mol Sci"},{"issue":"5","key":"1539_CR71","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1002\/path.4684","volume":"238","author":"GS Tejeda","year":"2016","unstructured":"Tejeda GS, Ayuso-Dolado S, Arbeteta R, Esteban-Ortega GM, Vidaurre OG, Diaz-Guerra M. Brain ischaemia induces shedding of a BDNF-scavenger ectodomain from TrkB receptors by excitotoxicity activation of metalloproteinases and gamma-secretases. J Pathol. 2016;238(5):627\u201340.","journal-title":"J Pathol"},{"issue":"7","key":"1539_CR73","doi-asserted-by":"publisher","first-page":"e9950","DOI":"10.15252\/emmm.201809950","volume":"11","author":"GS Tejeda","year":"2019","unstructured":"Tejeda GS, Esteban-Ortega GM, San Antonio E, Vidaurre OGG, D\u00edaz-Guerra M. Prevention of excitotoxicity-induced processing of BDNF receptor TrkB-FL leads to stroke neuroprotection. EMBO Mol Med. 2019;11(7):e9950.","journal-title":"EMBO Mol Med"},{"issue":"4","key":"1539_CR74","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.1073\/pnas.1220978110","volume":"110","author":"DA Thayer","year":"2013","unstructured":"Thayer DA, Jan YN, Jan LY. Increased neuronal activity fragments the Golgi complex. Proc Natl Acad Sci U S A. 2013;110(4):1482\u20137.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"12","key":"1539_CR75","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1080\/17460441.2020.1806232","volume":"15","author":"I Varela-Nieto","year":"2020","unstructured":"Varela-Nieto I, Murillo-Cuesta S, Calvino M, Cediel R, Lassaletta L. Drug development for noise-induced hearing loss. Expert Opin Drug Discov. 2020;15(12):1457\u201371.","journal-title":"Expert Opin Drug Discov"},{"issue":"5","key":"1539_CR76","doi-asserted-by":"publisher","first-page":"375","DOI":"10.2174\/1567201817666200415111755","volume":"17","author":"BS Varnamkhasti","year":"2020","unstructured":"Varnamkhasti BS, Jafari S, Taghavi F, Alaei L, Izadi Z, Lotfabadi A, et al. Cell-penetrating peptides: as a promising theranostics strategy to circumvent the blood-brain barrier for CNS diseases. Curr Drug Deliv. 2020;17(5):375\u201386.","journal-title":"Curr Drug Deliv"},{"issue":"1","key":"1539_CR77","doi-asserted-by":"publisher","first-page":"e256","DOI":"10.1038\/cddis.2011.143","volume":"3","author":"OG Vidaurre","year":"2012","unstructured":"Vidaurre OG, Gascon S, Deogracias R, Sobrado M, Cuadrado E, Montaner J, et al. Imbalance of neurotrophin receptor isoforms TrkB-FL\/TrkB-T1 induces neuronal death in excitotoxicity. Cell Death Dis. 2012;3(1):e256.","journal-title":"Cell Death Dis"},{"key":"1539_CR78","doi-asserted-by":"publisher","first-page":"108895","DOI":"10.1016\/j.heares.2023.108895","volume":"439","author":"HA Vink","year":"2023","unstructured":"Vink HA, Ramekers D, Foster AC, Versnel H. The efficacy of a TrkB monoclonal antibody agonist in preserving the auditory nerve in deafened guinea pigs. Hear Res. 2023;439:108895.","journal-title":"Hear Res"},{"key":"1539_CR79","doi-asserted-by":"publisher","first-page":"e03564","DOI":"10.7554\/eLife.03564","volume":"3","author":"G Wan","year":"2014","unstructured":"Wan G, Gomez-Casati ME, Gigliello AR, Liberman MC, Corfas G. Neurotrophin-3 regulates ribbon synapse density in the cochlea and induces synapse regeneration after acoustic trauma. Elife. 2014;3:e03564.","journal-title":"Elife"},{"issue":"21","key":"1539_CR80","doi-asserted-by":"publisher","first-page":"7938","DOI":"10.1523\/JNEUROSCI.1434-10.2011","volume":"31","author":"Q Wang","year":"2011","unstructured":"Wang Q, Green SH. Functional role of neurotrophin-3 in synapse regeneration by spiral ganglion neurons on inner hair cells after excitotoxic trauma in vitro. J Neurosci. 2011;31(21):7938\u201349.","journal-title":"J Neurosci"},{"issue":"3","key":"1539_CR81","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1111\/j.1471-4159.2007.04606.x","volume":"102","author":"Y Wang","year":"2007","unstructured":"Wang Y, Liu L, Xia Z. Brain-derived neurotrophic factor stimulates the transcriptional and neuroprotective activity of myocyte-enhancer factor 2\u00a0C through an ERK1\/2-RSK2 signaling cascade. J Neurochem. 2007;102(3):957\u201366.","journal-title":"J Neurochem"},{"key":"1539_CR82","doi-asserted-by":"publisher","first-page":"6","DOI":"10.3389\/fnsyn.2014.00006","volume":"6","author":"A Yoshii","year":"2014","unstructured":"Yoshii A, Constantine-Paton M. Postsynaptic localization of PSD-95 is regulated by all three pathways downstream of TrkB signaling. Front Synaptic Neurosci. 2014;6:6.","journal-title":"Front Synaptic Neurosci"},{"issue":"32","key":"1539_CR83","doi-asserted-by":"publisher","first-page":"13042","DOI":"10.1523\/JNEUROSCI.0854-13.2013","volume":"33","author":"Q Yu","year":"2013","unstructured":"Yu Q, Chang Q, Liu X, Wang Y, Li H, Gong S, et al. Protection of spiral ganglion neurons from degeneration using small-molecule TrkB receptor agonists. J Neurosci. 2013;33(32):13042\u201352.","journal-title":"J Neurosci"},{"key":"1539_CR84","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.npbr.2019.03.001","volume":"32","author":"MN Zakaria","year":"2019","unstructured":"Zakaria MN, Abdul Wahab NA, Maamor N, Jalaei B, Dzulkarnain AAA. Auditory brainstem response (ABR) findings in males and females with comparable head sizes at supra-threshold and threshold levels. Neurol Psychiatry Brain Res. 2019;32:4\u20137.","journal-title":"Neurol Psychiatry Brain Res"}],"container-title":["Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s10020-026-01539-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-026-01539-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-026-01539-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T03:49:23Z","timestamp":1789616963000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s10020-026-01539-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,29]]},"references-count":84,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1539"],"URL":"https:\/\/doi.org\/10.1186\/s10020-026-01539-9","relation":{},"ISSN":["1528-3658"],"issn-type":[{"value":"1528-3658","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,29]]},"assertion":[{"value":"27 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study has no human data. Animal studies were approved by ethics committees from Consejo Superior de Investigaciones Cient\u00edficas (CSIC) and Comunidad de Madrid (Ref PROEX 325.4\/21) and comply with European (2010\/63\/EU) and Spanish (RD 53\/2013) regulations.","order":1,"name":"Ethics","label":"Ethics approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"N\/A.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"148"}}