{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:59:10Z","timestamp":1787018350379,"version":"build-2736575974"},"reference-count":39,"publisher":"American Society for Clinical Investigation","issue":"3","license":[{"start":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T00:00:00Z","timestamp":1612742400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,2,8]]},"abstract":"<jats:p>TrkB agonist drugs are shown here to have a significant effect on the regeneration of afferent cochlear synapses after noise-induced synaptopathy. The effects were consistent with regeneration of cochlear synapses that we observed in vitro after synaptic loss due to kainic acid\u2013induced glutamate toxicity and were elicited by administration of TrkB agonists, amitriptyline, and 7,8-dihydroxyflavone, directly into the cochlea via the posterior semicircular canal 48 hours after exposure to noise. Synaptic counts at the inner hair cell and wave 1 amplitudes in the auditory brainstem response (ABR) were partially restored 2 weeks after drug treatment. Effects of amitriptyline on wave 1 amplitude and afferent auditory synapse numbers in noise-exposed ears after systemic (as opposed to local) delivery were profound and long-lasting; synapses in the treated animals remained intact 1 year after the treatment. However, the effect of systemically delivered amitriptyline on synaptic rescue was dependent on dose and the time window of administration: it was only effective when given before noise exposure at the highest injected dose. The long-lasting effect and the efficacy of postexposure treatment indicate a potential broad application for the treatment of synaptopathy, which often goes undetected until well after the original damaging exposures.<\/jats:p>","DOI":"10.1172\/jci.insight.142572","type":"journal-article","created":{"date-parts":[[2020,12,29]],"date-time":"2020-12-29T12:02:50Z","timestamp":1609243370000},"source":"Crossref","is-referenced-by-count":34,"title":["Trk agonist drugs rescue noise-induced hidden hearing loss"],"prefix":"10.1172","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0522-388X","authenticated-orcid":true,"given":"Katharine A.","family":"Fernandez","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Eaton-Peabody Laboratories, Massachusetts Eye and Ear, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7050-1121","authenticated-orcid":true,"given":"Takahisa","family":"Watabe","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Eaton-Peabody Laboratories, Massachusetts Eye and Ear, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjie","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Eaton-Peabody Laboratories, Massachusetts Eye and Ear, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiankai","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Eaton-Peabody Laboratories, Massachusetts Eye and Ear, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohsuke","family":"Tani","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Eaton-Peabody Laboratories, Massachusetts Eye and Ear, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon G.","family":"Kujawa","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Eaton-Peabody Laboratories, Massachusetts Eye and Ear, Boston, Massachusetts, USA."},{"name":"Program in Speech and Hearing Bioscience and Technology, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8641-755X","authenticated-orcid":true,"given":"Albert S.B.","family":"Edge","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Eaton-Peabody Laboratories, Massachusetts Eye and Ear, Boston, Massachusetts, USA."},{"name":"Program in Speech and Hearing Bioscience and Technology, Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Harvard Stem Cell Institute, Cambridge, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2021,2,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4985-05.2006"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2845-09.2009"},{"issue":"3 pt 1","key":"B3","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/S0194-5998(97)70178-5","article-title":"Patterns of neural degeneration in the human cochlea and auditory nerve: implications for cochlear implantation","volume":"117","author":"Nadol","year":"1997","journal-title":"Otolaryngol Head Neck Surg"},{"issue":"1\u20132","key":"B4","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.heares.2006.08.017","article-title":"Physiology, pharmacology and plasticity at the inner hair cell synaptic complex","volume":"227","author":"Ruel","year":"2007","journal-title":"Hear Res"},{"issue":"34","key":"B5","doi-asserted-by":"crossref","first-page":"13686","DOI":"10.1523\/JNEUROSCI.1783-13.2013","article-title":"Age-related cochlear synaptopathy: an early-onset contributor to auditory functional decline","volume":"33","author":"Sergeyenko","year":"2013","journal-title":"J Neurosci"},{"issue":"3","key":"B6","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1007\/s101620020028","article-title":"Dynamics of noise-induced cellular injury and repair in the mouse cochlea","volume":"3","author":"Wang","year":"2002","journal-title":"J Assoc Res Otolaryngol"},{"key":"B7","doi-asserted-by":"crossref","DOI":"10.3389\/fnagi.2015.00058","article-title":"Mechanisms of sensorineural cell damage, death and survival in the cochlea","volume":"7","author":"Wong","year":"2015","journal-title":"Front Aging Neurosci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2019.11.051"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0096-15.2015"},{"issue":"2","key":"B10","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/cne.20564","article-title":"Chronic depolarization enhances the trophic effects of brain-derived neurotrophic factor in rescuing auditory neurons following a sensorineural hearing loss","volume":"486","author":"Shepherd","year":"2005","journal-title":"J Comp Neurol"},{"issue":"3","key":"B11","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1073\/pnas.032677999","article-title":"Neurotrophic factor intervention restores auditory function in deafened animals","volume":"99","author":"Shinohara","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"B12","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1002\/cne.20563","article-title":"Resprouting and survival of guinea pig cochlear neurons in response to the administration of the neurotrophins brain-derived neurotrophic factor and neurotrophin-3","volume":"487","author":"Wise","year":"2005","journal-title":"J Comp Neurol"},{"issue":"2","key":"B13","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/0169-328X(95)00250-V","article-title":"Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF","volume":"36","author":"Poduslo","year":"1996","journal-title":"Brain Res Mol Brain Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2009.05.010"},{"key":"B15","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.brainres.2007.01.090","article-title":"Administration of amitriptyline attenuates noise-induced hearing loss via glial cell line-derived neurotrophic factor (GDNF) induction","volume":"1144","author":"Shibata","year":"2007","journal-title":"Brain Res"},{"issue":"3","key":"B16","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.bbrc.2012.04.154","article-title":"7,8,3\u2032-Trihydroxyflavone, a potent small molecule TrkB receptor agonist, protects spiral ganglion neurons from degeneration both in vitro and in vivo","volume":"422","author":"Yu","year":"2012","journal-title":"Biochem Biophys Res Commun"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0854-13.2013"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/neu.20232"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s10162-013-0374-3"},{"issue":"21","key":"B20","doi-asserted-by":"crossref","first-page":"7938","DOI":"10.1523\/JNEUROSCI.1434-10.2011","article-title":"Functional role of neurotrophin-3 in synapse regeneration by spiral ganglion neurons on inner hair cells after excitotoxic trauma in vitro","volume":"31","author":"Wang","year":"2011","journal-title":"J Neurosci"},{"issue":"2","key":"B21","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/0378-5955(85)90006-1","article-title":"Kainic acid selectively alters auditory dendrites connected with cochlear inner hair cells","volume":"18","author":"Pujol","year":"1985","journal-title":"Hear Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1999.tb08646.x"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5138-14.2015"},{"issue":"pt B","key":"B24","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.heares.2015.02.009","article-title":"Synaptopathy in the noise-exposed and aging cochlea: primary neural degeneration in acquired sensorineural hearing loss","volume":"330","author":"Kujawa","year":"2015","journal-title":"Hear Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/bies.20502"},{"issue":"11","key":"B26","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1002\/ar.22587","article-title":"The Trk A, B, C\u2019s of neurotrophins in the cochlea","volume":"295","author":"Green","year":"2012","journal-title":"Anat Rec (Hoboken)"},{"issue":"10","key":"B27","doi-asserted-by":"crossref","first-page":"2575","DOI":"10.1523\/JNEUROSCI.5514-03.2004","article-title":"NT-3 replacement with brain-derived neurotrophic factor redirects vestibular nerve fibers to the cochlea","volume":"24","author":"Tessarollo","year":"2004","journal-title":"J Neurosci"},{"issue":"16","key":"B28","doi-asserted-by":"crossref","first-page":"6213","DOI":"10.1523\/JNEUROSCI.17-16-06213.1997","article-title":"Lack of neurotrophin 3 causes losses of both classes of spiral ganglion neurons in the cochlea in a region-specific fashion","volume":"17","author":"Fritzsch","year":"1997","journal-title":"J Neurosci"},{"issue":"39","key":"B29","doi-asserted-by":"crossref","first-page":"17005","DOI":"10.1073\/pnas.1008938107","article-title":"Nonneuronal cells regulate synapse formation in the vestibular sensory epithelium via erbB-dependent BDNF expression","volume":"107","author":"Gomez-Casati","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B30","doi-asserted-by":"crossref","DOI":"10.1038\/srep24907","article-title":"Round-window delivery of neurotrophin 3 regenerates cochlear synapses after acoustic overexposure","volume":"6","author":"Suzuki","year":"2016","journal-title":"Sci Rep"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.03564"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2014.01.047"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.09.031"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-1019525"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.1977.01770140126014"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1126\/science.202024"},{"issue":"36","key":"B37","doi-asserted-by":"crossref","DOI":"10.3791\/1685","article-title":"Primary culture and plasmid electroporation of the murine organ of Corti","volume":"2010","author":"Parker","year":"1685","journal-title":"J Vis Exp"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.22136"},{"issue":"1\u20132","key":"B39","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.heares.2004.08.011","article-title":"A physiological place-frequency map of the cochlea in the CBA\/J mouse","volume":"202","author":"Muller","year":"2005","journal-title":"Hear Res"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/142572\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:47:55Z","timestamp":1779151675000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/142572"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,8]]},"references-count":39,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,2,8]]},"published-print":{"date-parts":[[2021,2,8]]}},"alternative-id":["10.1172\/jci.insight.142572"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.142572","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.07.01.182931","asserted-by":"object"}]},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,8]]},"article-number":"e142572"}}