{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:07:58Z","timestamp":1753891678418,"version":"3.41.2"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T00:00:00Z","timestamp":1739145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R01DC019158"],"award-info":[{"award-number":["5R01DC019158"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"Department of Veterans Affairs","doi-asserted-by":"publisher","award":["5I01RX003532"],"award-info":[{"award-number":["5I01RX003532"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Despite the high prevalence of noise-induced hearing loss (NIHL), no effective treatments exist currently. Underlying mechanisms behind NIHL include elevated reactive oxygen species and inflammation, all which ultimately lead to cellular apoptosis. Z-VAD-FMK, an apoptosis inhibitor, has demonstrated protective effects against cochlear hair cells exposed to ototoxic agents; however, its potential for treating NIHL remains unexplored. This study assessed the efficacy of Z-VAD-FMK as a therapeutic for noise-induced cochlear injury in a rodent model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Rodents were assigned to one of four groups: (1) unexposed, (2) noise-exposed, (3) noise + vehicle, and (4) noise + Z-VAD-FMK. Noise delivery consisted of 1\u202fh of 110 dB continuous white-noise, with Z-VAD-FMK administered intraperitoneally 6\u202fh afterward. Auditory brainstem responses (ABRs), cochlear hair cell density, and protein levels were evaluated post-interventions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Noise exposure caused a permanent threshold shift across all frequencies, with minimal recovery by day 28. However, post-exposure treatment with Z-VAD-FMK significantly mitigated ABR threshold, amplitudes, and latencies shifts particularly at low and mid frequencies. Treatment rescued outer hair cells across middle and basal cochlear turns and reduced caspase-9 and IL-1\u03b2 levels, as indicated by protein analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings indicate that a single intraperitoneal injection of Z-VAD-FMK can partially mitigate cochlear dysfunction induced by acoustic overexposure in a rodent model, highlighting its potential as a therapeutic intervention for NIHL.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnins.2025.1497773","type":"journal-article","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T06:50:28Z","timestamp":1739170228000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Pan-caspase inhibitor protects against noise-induced hearing loss in a rodent model"],"prefix":"10.3389","volume":"19","author":[{"given":"Maria Fernanda","family":"Yepes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kayla","family":"Minesinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica M.","family":"Raciti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Camila","family":"Salazar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suhrud M.","family":"Rajguru","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,10]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1007\/s00405-011-1487-0","article-title":"Intracochlear perfusion of leupeptin and Z-VAD-FMK: influence of antiapoptotic agents on gunshot-induced hearing loss","volume":"268","author":"Abaamrane","year":"2011","journal-title":"Eur. Arch. Otorrinolaringol."},{"key":"ref2","doi-asserted-by":"crossref","first-page":"2S17","DOI":"10.3109\/14992020309074639","article-title":"Negative consequences of uncorrected hearing loss\u2014a review","volume":"42","author":"Arlinger","year":"2003","journal-title":"Int. J. Audiol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1016\/S0140-6736(13)61613-X","article-title":"Auditory and non-auditory effects of noise on health","volume":"383","author":"Basner","year":"2014","journal-title":"Lancet"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1921","DOI":"10.1007\/s00405-019-05417-5","article-title":"Protective and therapeutic effects of milrinone on acoustic trauma in rat cochlea","volume":"276","author":"Ceylan","year":"2019","journal-title":"Eur. Arch. Otorrinolaringol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1080\/00016489.2017.1280850","article-title":"Effects of early intratympanic steroid injection in patients with acoustic trauma caused by gunshot noise","volume":"137","author":"Chang","year":"2017","journal-title":"Acta Otolaryngol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"135089","DOI":"10.1016\/j.neulet.2020.135089","article-title":"Caspase inhibitor Z-VAD-FMK increases the survival of hair cells after actinomycin-D-induced damage in vitro","volume":"732","author":"Chang","year":"2020","journal-title":"Neurosci. Lett."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/sj.cdd.4402044","article-title":"Broad-spectrum caspase inhibitors: from myth to reality?","volume":"14","author":"Chauvier","year":"2007","journal-title":"Cell Death Differ."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/s10162-002-3016-8","article-title":"Hair cell death in the avian basilar papilla: characterization of the in vitro model and caspase activation","volume":"4","author":"Cheng","year":"2003","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1017\/S002221511900121X","article-title":"Comparison of oral steroid regimens for acute acoustic trauma caused by gunshot noise exposure","volume":"133","author":"Choi","year":"2019","journal-title":"J. Laryngol. Otol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"8532","DOI":"10.1523\/JNEUROSCI.22-19-08532.2002","article-title":"Caspase activation in hair cells of the mouse utricle exposed to neomycin","volume":"22","author":"Cunningham","year":"2002","journal-title":"J. Neurosci."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1161\/01.CIR.69.5.1026","article-title":"The effects of milrinone on conduction, reflection, and automaticity in canine Purkinje fibers","volume":"69","author":"Davidenko","year":"1984","journal-title":"Circulation"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1002\/(SICI)1097-4652(199902)178:2<133::AID-JCP2>3.0.CO;2-5","article-title":"Function of caspases in regulating apoptosis caused by erythropoietin deprivation in erythroid progenitors","volume":"178","author":"Gregoli","year":"1999","journal-title":"J. Cell. Physiol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/S0378-5955(02)00286-1","article-title":"Involvement of apoptosis in progression of cochlear lesion following exposure to intense noise","volume":"166","author":"Hu","year":"2002","journal-title":"Hear. Res."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.heares.2005.08.006","article-title":"Extremely rapid induction of outer hair cell apoptosis in the chinchilla cochlea following exposure to impulse noise","volume":"211","author":"Hu","year":"2006","journal-title":"Hear. Res."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/S0014-2999(00)00477-5","article-title":"In vivo myocardial infarct size reduction by a caspase inhibitor administered after the onset of ischemia","volume":"402","author":"Huang","year":"2000","journal-title":"Eur. J. Pharmacol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"2077","DOI":"10.1182\/blood-2002-03-0752","article-title":"The caspase inhibitor Z-VAD is more effective than CD18 adhesion blockade in reducing muscle ischemia-reperfusion injury: implication for clinical trials","volume":"100","author":"Iwata","year":"2002","journal-title":"Blood"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"192","DOI":"10.3389\/fncel.2017.00192","article-title":"Resolution of cochlear inflammation: novel target for preventing or ameliorating drug-, noise-and age-related hearing loss","volume":"11","author":"Kalinec","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1097\/MAO.0b013e3182267e06","article-title":"Protective effects of pentoxifylline and nimodipine on acoustic trauma in guinea pig cochlea","volume":"32","author":"Kansu","year":"2011","journal-title":"Otol. Neurotol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"e971","DOI":"10.1097\/MAO.0000000000002760","article-title":"Hearing outcomes of treatment for acute noise-induced hearing loss: a systematic review and meta-analysis","volume":"41","author":"Koochakzadeh","year":"2020","journal-title":"Otol. Neurotol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/S0378-5955(00)00176-3","article-title":"Reduction of noise-induced hearing loss using L-NAC and salicylate in the chinchilla","volume":"149","author":"Kopke","year":"2000","journal-title":"Hear. Res."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"14077","DOI":"10.1523\/JNEUROSCI.2845-09.2009","article-title":"Adding insult to injury: cochlear nerve degeneration after \u201ctemporary\u201d noise-induced hearing loss","volume":"29","author":"Kujawa","year":"2009","journal-title":"J. Neurosci."},{"key":"ref22","first-page":"63","article-title":"Hyperbaric oxygen therapy for acute noise-induced hearing loss: evaluation of different treatment regimens","volume":"40","author":"Laf\u00e8re","year":"2010","journal-title":"Diving Hyperb. Med."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/s40463-017-0219-x","article-title":"Current insights in noise-induced hearing loss: a literature review of the underlying mechanism, pathophysiology, asymmetry, and management options","volume":"46","author":"Le","year":"2017","journal-title":"J. Otolaryngol. Head Neck Surg."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1007\/s10162-014-0441-4","article-title":"Antioxidants reduce cellular and functional changes induced by intense noise in the inner ear and cochlear nucleus","volume":"15","author":"Lu","year":"2014","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"6111","DOI":"10.1523\/JNEUROSCI.23-14-06111.2003","article-title":"Caspase inhibitors promote vestibular hair cell survival and function after aminoglycoside treatment in vivo","volume":"23","author":"Matsui","year":"2003","journal-title":"J. Neurosci."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.heares.2004.10.011","article-title":"Dietary vitamin C supplementation reduces noise-induced hearing loss in guinea pigs","volume":"202","author":"McFadden","year":"2005","journal-title":"Hear. Res."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1080\/15459620590932154","article-title":"The effectiveness of hearing protection among construction workers","volume":"2","author":"Neitzel","year":"2005","journal-title":"J. Occup. Environ. Hyg."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1007\/s10162-002-3038-2","article-title":"The caspase pathway in noise-induced apoptosis of the chinchilla cochlea","volume":"4","author":"Nicotera","year":"2003","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/S0006-8993(00)02733-5","article-title":"Intense noise induces formation of vasoactive lipid peroxidation products in the cochlea","volume":"878","author":"Ohinata","year":"2000","journal-title":"Brain Res."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1159\/000013846","article-title":"Early elevation of cochlear reactive oxygen species following noise exposure","volume":"4","author":"Ohlemiller","year":"1999","journal-title":"Audiol. Neurootol."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.anl.2004.11.006","article-title":"Inhibition of caspases alleviates gentamicin-induced cochlear damage in guinea pigs","volume":"32","author":"Okuda","year":"2005","journal-title":"Auris Nasus Larynx"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"261","DOI":"10.3389\/fncel.2019.00261","article-title":"Inner ear therapeutics: an overview of middle ear delivery","volume":"13","author":"Patel","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1523\/JNEUROSCI.20-01-00043.2000","article-title":"Rescue of hearing, auditory hair cells, and neurons by CEP-1347\/KT7515, an inhibitor of c-Jun N-terminal kinase activation","volume":"20","author":"Pirvola","year":"2000","journal-title":"J. Neurosci."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.3390\/life13041035","article-title":"Antioxidant therapy as an effective strategy against noise-induced hearing loss: from experimental models to clinic","volume":"13","author":"Pisani","year":"2023","journal-title":"Life"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.1097\/00001756-199806220-00037","article-title":"Excitotoxicity and repair of cochlear synapses after noise-trauma induced hearing loss","volume":"9","author":"Puel","year":"1998","journal-title":"Neuroreport"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"330","DOI":"10.3109\/00016489309135819","article-title":"Pathophysiology of the glutamatergic synapses in the cochlea","volume":"113","author":"Pujol","year":"1993","journal-title":"Acta Otolaryngol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/0378-5955(94)90189-9","article-title":"Lipid peroxidation inhibitor attenuates noise-induced temporary threshold shifts","volume":"74","author":"Quirk","year":"1994","journal-title":"Hear. Res."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"4089","DOI":"10.1007\/s00405-016-3936-2","article-title":"Pharmacological agents used for treatment and prevention in noise-induced hearing loss","volume":"273","author":"Sakat","year":"2016","journal-title":"Eur. Arch. Otorrinolaringol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1016\/S0092-8674(00)80430-4","article-title":"Caspases: intracellular signaling by proteolysis","volume":"91","author":"Salvesen","year":"1997","journal-title":"Cell"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.heares.2006.12.011","article-title":"Prophylactic and therapeutic functions of T-type calcium blockers against noise-induced hearing loss","volume":"226","author":"Shen","year":"2007","journal-title":"Hear. Res."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.heares.2016.01.010","article-title":"Pathophysiology of the cochlear intrastrial fluid-blood barrier (review)","volume":"338","author":"Shi","year":"2016","journal-title":"Hear. Res."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1315S","DOI":"10.1093\/ajcn\/62.6.1315S","article-title":"Vitamins E and C, beta-carotene, and other carotenoids as antioxidants","volume":"62","author":"Sies","year":"1995","journal-title":"Am. J. Clin. Nutr."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1089\/ther.2019.0034","article-title":"Additive protective effects of delayed mild therapeutic hypothermia and antioxidants on PC12 cells exposed to oxidative stress","volume":"11","author":"Singh","year":"2021","journal-title":"Ther. Hypothermia Temp. Manag."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1002\/(SICI)1097-0274(200004)37:4<334::AID-AJIM2>3.0.CO;2-Z","article-title":"Comparison of NIOSH noise criteria and OSHA hearing conservation criteria","volume":"37","author":"Sriwattanatamma","year":"2000","journal-title":"Am. J. Ind. Med."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1097\/MOO.0000000000000079","article-title":"Noise-induced hearing loss: an occupational medicine perspective","volume":"22","author":"Stucken","year":"2014","journal-title":"Curr. Opin. Otolaryngol. Head Neck Surg."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.heares.2004.06.003","article-title":"Direct inner ear infusion of dexamethasone attenuates noise-induced trauma in guinea pig","volume":"196","author":"Takemura","year":"2004","journal-title":"Hear. Res."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"CD006396","DOI":"10.1002\/14651858.CD006396.pub4","article-title":"Interventions to prevent occupational noise-induced hearing loss","volume":"2019","author":"Tikka","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/S0378-5955(01)00391-4","article-title":"Oxidative DNA damage is associated with intense noise exposure in the rat","volume":"164","author":"Van Campen","year":"2002","journal-title":"Hear. Res."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.heares.2018.09.002","article-title":"A comparison of systemic and local dexamethasone administration: from perilymph\/cochlea concentration to cochlear distribution","volume":"370","author":"Wang","year":"2018","journal-title":"Hear. Res."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"106","DOI":"10.3389\/fncel.2017.00106","article-title":"The contribution of immune infiltrates to ototoxicity and cochlear hair cell loss","volume":"11","author":"Wood","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1002\/(SICI)1097-4547(19960801)45:3<282::AID-JNR10>3.0.CO;2-6","article-title":"Neuroprotective effects of hypothermia and U-78517F in cerebral ischemia are due to reducing oxygen-based free radicals: an electron paramagnetic resonance study with gerbils","volume":"45","author":"Zhao","year":"1996","journal-title":"J. Neurosci. Res."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1159\/000522051","article-title":"Efficacy of oral steroids for acute acoustic trauma","volume":"27","author":"Zloczower","year":"2022","journal-title":"Audiol. 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