{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T04:25:41Z","timestamp":1787631941971,"version":"build-2736575974"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T00:00:00Z","timestamp":1626220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003360","name":"Ligue Genevoise Contre le Cancer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003360","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>Cisplatin is a lifesaving chemotherapeutic drug with marked ototoxic adverse effects. Cisplatin-induced hearing loss affects a significant part of cancer-surviving patients and is an unmet clinical need with important socioeconomic consequences. Unfortunately, in current preclinical animal models of cisplatin ototoxicity, which are mainly based on systemic delivery, important morbidity is observed, leading to premature death. This methodology not only raises obvious animal welfare concerns but also increases the number of animals used in ototoxicity studies to compensate for dropouts related to early death. To overcome these important limitations, we developed a local delivery model based on the application of a cisplatin solution directly into the otic bulla through a retroauricular approach. The local delivery model reliably induced significant hearing loss with a mean threshold shift ranging from 10 to 30 dB, strongly affecting the high frequencies (22 and 32 kHz). Importantly, mice did not show visible stress or distress indicators and no significant morbidity in comparison with a traditional systemic delivery control group of mice injected intraperitoneally with 10 mg\/kg cisplatin, where significant weight loss &amp;gt;10% in all treated animals (without any recovery) led to premature abortion of experiments on day 3. Mass spectrometry confirmed the absence of relevant systemic uptake after local delivery, with platinum accumulation restricted to the cochlea, whereas important platinum concentrations were detected in the liver and kidney of the systemic cisplatin group. A clear correlation between the cochlear platinum concentration and the auditory threshold shift was observed. Immunohistochemistry revealed statistically significant loss of outer hair cells in the basal and apical turns of the cochlea and an important and statistically significant loss of auditory neurons and synapses in all cochlear regions. In conclusion, local cisplatin delivery induces robust hearing loss with minimal morbidity, thereby offering a reliable rodent model for human cisplatin ototoxicity, reducing the number of animals required and showing improved animal welfare compared with traditional systemic models.<\/jats:p>","DOI":"10.3389\/fncel.2021.701783","type":"journal-article","created":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T03:00:46Z","timestamp":1626231646000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Local Cisplatin Delivery in Mouse Reliably Models Sensorineural Ototoxicity Without Systemic Adverse Effects"],"prefix":"10.3389","volume":"15","author":[{"given":"German","family":"Nacher-Soler","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Lenglet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Coelho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lien","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Voruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl-Heinz","family":"Krause","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Senn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Rousset","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"311","DOI":"10.4103\/0019-509x.55551","article-title":"Cisplatin-based chemotherapy: add high-frequency audiometry in the regimen.","volume":"46","author":"Arora","year":"2009","journal-title":"Indian J. Cancer"},{"key":"B2","doi-asserted-by":"crossref","first-page":"201367","DOI":"10.4061\/2010\/201367","article-title":"Cellular responses to cisplatin-induced DNA damage.","volume":"2010","author":"Basu","year":"2010","journal-title":"J. Nucleic Acids"},{"key":"B3","doi-asserted-by":"crossref","first-page":"10889","DOI":"10.1038\/s41598-019-47433-9","article-title":"Cochlear shape reveals that the human organ of hearing is sex-typed from birth.","volume":"9","author":"Braga","year":"2019","journal-title":"Sci. Rep."},{"key":"B4","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1038\/s41467-017-01837-1","article-title":"Cisplatin is retained in the cochlea indefinitely following chemotherapy.","volume":"8","author":"Breglio","year":"2017","journal-title":"Nat. Commun."},{"key":"B5","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/j.ejphar.2014.07.025","article-title":"Cisplatin in cancer therapy: molecular mechanisms of action.","volume":"740","author":"Dasari","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"107878","DOI":"10.1016\/j.heares.2019.107878","article-title":"Cisplatin-induced threshold shift in the CBA\/CaJ, C57BL\/6J, BALB\/cJ mouse models of hearing loss.","volume":"387","author":"DeBacker","year":"2020","journal-title":"Hear. Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"4104","DOI":"10.1158\/1078-0432.ccr-18-3179","article-title":"Clinical and genome-wide analysis of cisplatin-induced tinnitus implicates novel ototoxic mechanisms.","volume":"25","author":"El Charif","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.heares.2019.02.006","article-title":"An optimized, clinically relevant mouse model of cisplatin-induced ototoxicity.","volume":"375","author":"Fernandez","year":"2019","journal-title":"Hear. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.toxlet.2015.06.012","article-title":"An integrated view of cisplatin-induced nephrotoxicity and ototoxicity.","volume":"237","author":"Karasawa","year":"2015","journal-title":"Toxicol. Lett."},{"key":"B10","doi-asserted-by":"publisher","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":"B11","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.1002\/cncr.29779","article-title":"Ototoxicity and cancer therapy.","volume":"122","author":"Landier","year":"2016","journal-title":"Cancer"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1709","DOI":"10.1002\/pbc.24560","article-title":"Speech recognition and frequency of hearing loss in patients treated for cancer in childhood.","volume":"60","author":"Liberman","year":"2013","journal-title":"Pediatr. Blood Cancer"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.1089\/ars.2017.7288","article-title":"Wnt signaling activates TP53-induced glycolysis and apoptosis regulator and protects against cisplatin-induced spiral ganglion neuron damage in the mouse cochlea.","volume":"30","author":"Liu","year":"2019","journal-title":"Antioxid. Redox Signal."},{"key":"B14","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1097\/mao.0b013e318191bff8","article-title":"Entry of substances into perilymph through the bone of the otic capsule after intratympanic applications in guinea pigs: implications for local drug delivery in humans.","volume":"30","author":"Mikulec","year":"2009","journal-title":"Otol. Neurotol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2490","DOI":"10.3390\/toxins2112490","article-title":"Mechanisms of cisplatin nephrotoxicity.","volume":"2","author":"Miller","year":"2010","journal-title":"Toxins (Basel)"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1662","DOI":"10.1002\/hed.23201","article-title":"Characteristics of radiation-induced sensorineural hearing loss in head and neck cancer: a systematic review.","volume":"35","author":"Mujica-Mota","year":"2013","journal-title":"Head Neck"},{"key":"B17","doi-asserted-by":"publisher","first-page":"200","DOI":"10.4274\/balkanmedj.2016.0226","article-title":"Retroauricular approach for targeted cochlear therapy experiments in wistar albino rats.","volume":"34","author":"Mulazimoglu","year":"2017","journal-title":"Balkan Med. J."},{"key":"B18","first-page":"54951","article-title":"A comparative study of drug delivery methods targeted to the mouse inner ear: bullostomy versus transtympanic injection.","volume":"121","author":"Murillo-Cuesta","year":"2017","journal-title":"J. Vis. Exp."},{"key":"B19","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1097\/mao.0000000000002417","article-title":"Intratympanic diltiazem-chitosan hydrogel as an otoprotectant against cisplatin-induced ototoxicity in a mouse model.","volume":"41","author":"Naples","year":"2020","journal-title":"Otol. Neurotol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1038\/nrneurol.2015.12","article-title":"Age-related hearing impairment-a risk factor and frailty marker for dementia and AD.","volume":"11","author":"Panza","year":"2015","journal-title":"Nat. Rev. Neurol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1177\/0194599811409304","article-title":"Can intratympanic dexamethasone protect against cisplatin ototoxicity in mice with age-related hearing loss?","volume":"145","author":"Parham","year":"2011","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"B22","doi-asserted-by":"crossref","first-page":"4150","DOI":"10.1038\/s41467-019-12073-0","article-title":"GSTA4 mediates reduction of cisplatin ototoxicity in female mice.","volume":"10","author":"Park","year":"2019","journal-title":"Nat. Commun."},{"key":"B23","doi-asserted-by":"crossref","first-page":"e739","DOI":"10.1097\/MAO.0000000000002305","article-title":"Poly-lactic acid-based biopolymer formulations are safe for sustained intratympanic dexamethasone delivery.","volume":"40","author":"Rousset","year":"2019","journal-title":"Otol. Neurotol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"101434","DOI":"10.1016\/j.redox.2020.101434","article-title":"Redox activation of excitatory pathways in auditory neurons as mechanism of age-related hearing loss.","volume":"30","author":"Rousset","year":"2020","journal-title":"Redox Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1176\/appi.ajp.2017.17040423","article-title":"Sensation and psychiatry: linking age-related hearing loss to late-life depression and cognitive decline.","volume":"175","author":"Rutherford","year":"2018","journal-title":"Am. J. Psychiatry"},{"key":"B26","doi-asserted-by":"publisher","first-page":"338","DOI":"10.3389\/fncel.2017.00338","article-title":"Mechanisms of cisplatin-induced ototoxicity and otoprotection.","volume":"11","author":"Sheth","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"B27","first-page":"53131","article-title":"The mouse round-window approach for ototoxic agent delivery: a rapid and reliable technique for inducing cochlear cell degeneration.","volume":"105","author":"Stevens","year":"2015","journal-title":"J. Vis. Exp."},{"key":"B28","doi-asserted-by":"publisher","first-page":"118496","DOI":"10.1016\/j.ijpharm.2019.118496","article-title":"Pharmacokinetics and biodistribution study of self-assembled Gd-micelles demonstrating blood-pool contrast enhancement for MRI.","volume":"568","author":"Vorobiev","year":"2019","journal-title":"Int. J. Pharm."},{"key":"B29","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1097\/mao.0b013e318248ee66","article-title":"Gene therapy for cisplatin-induced ototoxicity: a systematic review of in vitro and experimental animal studies.","volume":"33","author":"Waissbluth","year":"2012","journal-title":"Otol. Neurotol."}],"container-title":["Frontiers in Cellular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2021.701783\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T03:00:56Z","timestamp":1626231656000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2021.701783\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,14]]},"references-count":29,"alternative-id":["10.3389\/fncel.2021.701783"],"URL":"https:\/\/doi.org\/10.3389\/fncel.2021.701783","relation":{},"ISSN":["1662-5102"],"issn-type":[{"value":"1662-5102","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,14]]},"article-number":"701783"}}