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Due to the heterogeneity of causes for SNHL, effective treatment options remain scarce, creating an unmet need for novel drugs in the field of otology. Cochlear implantation (CI) currently is the only established method to restore hearing function in profound SNHL and deaf patients. The cochlear implant bypasses the non-functioning sensory hair cells (HCs) and electrically stimulates the neurons of the cochlear nerve. CI also benefits patients with residual hearing by combined electrical and auditory stimulation. However, the insertion of an electrode array into the cochlea induces an inflammatory response, characterized by the expression of pro-inflammatory cytokines, upregulation of reactive oxygen species, and apoptosis and necrosis of HCs, putting residual hearing at risk. Here, we characterize the small molecule AC102, a pyridoindole, for its protective effects on residual hearing in CI. In a gerbil animal model of CI, AC102 significantly improves the recovery of hearing thresholds across multiple frequencies and confines the cochlear trauma to the directly mechanically injured area. In addition, AC102 significantly preserves auditory nerve fibers and inner HC synapses throughout the whole cochlea. In vitro experiments in an ethanol challenged HT22 cell-line revealed significant and dose-responsive anti-apoptotic effects following the treatment of with AC102. Further, AC102 treatment resulted in significant downregulation of the expression of pro-inflammatory cytokines in an organotypic ex vivo model of electrode insertion trauma (EIT). These results suggest that AC102\u2019s effects are likely elicited during the inflammatory phase of EIT and mediated by anti-apoptotic and anti-inflammatory properties, highlighting AC102 as a promising compound for hearing preservation during CI. Moreover, since the inflammatory response in CI shares similarities to that in other etiologies of SNHL, AC102 may be inferred as a potential general treatment option for various inner ear conditions.<\/jats:p>","DOI":"10.1038\/s41419-024-06854-9","type":"journal-article","created":{"date-parts":[[2024,7,27]],"date-time":"2024-07-27T00:03:07Z","timestamp":1722038587000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A preoperative dose of the pyridoindole AC102 improves the recovery of residual hearing in a gerbil animal model of cochlear implantation"],"prefix":"10.1038","volume":"15","author":[{"given":"Michael","family":"Nieratschker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9010-7124","authenticated-orcid":false,"given":"Erdem","family":"Yildiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Gerlitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5723-0091","authenticated-orcid":false,"given":"Sujoy","family":"Bera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anselm J.","family":"Gadenstaetter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Margarethe","family":"Kramer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8826-3919","authenticated-orcid":false,"given":"Monika","family":"Kwiatkowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0448-4730","authenticated-orcid":false,"given":"Pavel","family":"Mistrik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9660-2625","authenticated-orcid":false,"given":"Lukas D.","family":"Landegger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Braun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reimar","family":"Schlingensiepen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens","family":"Honeder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0066-810X","authenticated-orcid":false,"given":"Christoph","family":"Arnoldner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Rommelspacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,26]]},"reference":[{"key":"6854_CR1","unstructured":"WHO. 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MN, EY, AJG and MG were financed by this funding while conducting the studies. LDL receives research funding from Decibel Therapeutics\/Regeneron Pharmaceuticals and Amgen and has worked as an independent consultant for Gerson Lehrman Group and Conclave Capital. SBr and PM are employed by MED-EL as Senior Research Specialists and were involved in conceptualization of the study design. RS and HR are CEO and CSO of Audiocure Pharma GmbH, developing the compound AC102. Both had no involvement during conduction of the study or during analysis of the results. MK and SB are employees of Audiocure Pharma GmbH. The remaining authors declare no conflict of interest. The funding sources did not influence the study design, the interpretation of the data or the decision to publish this article.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Animal care, treatments and procedures were performed according to the guidelines of the Austrian Federal Ministry for Science, Research and Economy. All animal experiments were approved by the local animal welfare committee (66.009\/0094-V\/3b\/2019).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"531"}}