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We have previously conducted high-throughput screenings of bioactive compounds, using zebrafish as our discovery platform, and identified piplartine as a potential therapeutic molecule. In the present study, we expanded this work and characterized piplartine\u2019s physicochemical and therapeutic properties. We showed that piplartine had a wide therapeutic window and neither induced nephrotoxicity in vivo in zebrafish nor interfered with aminoglycoside antibacterial activity. In addition, a fluorescence-based assay demonstrated that piplartine did not inhibit cytochrome C activity in microsomes. Coadministration of piplartine protected from kanamycin-induced hair cell loss in zebrafish and protected hearing function, outer hair cells, and presynaptic ribbons in a mouse model of kanamycin ototoxicity. Last, we investigated piplartine\u2019s mechanism of action by phospho-omics, immunoblotting, immunohistochemistry, and molecular dynamics experiments. We found an up-regulation of AKT1 signaling in the cochleas of mice cotreated with piplartine. Piplartine treatment normalized kanamycin-induced up-regulation of TRPV1 expression and modulated the gating properties of this receptor. Because aminoglycoside entrance to the inner ear is, in part, mediated by TRPV1, these results suggested that by regulating TRPV1 expression, piplartine blocked aminoglycoside\u2019s entrance, thereby preventing the long-term deleterious effects of aminoglycoside accumulation in the inner ear compartment.<\/jats:p>","DOI":"10.1126\/scitranslmed.adn2140","type":"journal-article","created":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T18:02:45Z","timestamp":1723053765000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":15,"title":["Piplartine attenuates aminoglycoside-induced TRPV1 activity and protects from hearing loss in mice"],"prefix":"10.1126","volume":"16","author":[{"given":"Marisa","family":"Zallocchi","sequence":"first","affiliation":[{"name":"Creighton University School of Medicine, Omaha, NE 68178, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarath","family":"Vijayakumar","sequence":"additional","affiliation":[{"name":"Creighton University School of Medicine, Omaha, NE 68178, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Fleegel","sequence":"additional","affiliation":[{"name":"Creighton University School of Medicine, Omaha, NE 68178, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyudmila","family":"Batalkina","sequence":"additional","affiliation":[{"name":"Creighton University School of Medicine, Omaha, NE 68178, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katyarina E.","family":"Brunette","sequence":"additional","affiliation":[{"name":"Creighton University School of Medicine, Omaha, NE 68178, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhaval","family":"Shukal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Physiology, University of Z\u00fcrich, Z\u00fcrich CH-8057, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Devuyst","sequence":"additional","affiliation":[{"name":"Institute of Physiology, University of Z\u00fcrich, Z\u00fcrich CH-8057, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huizhan","family":"Liu","sequence":"additional","affiliation":[{"name":"Creighton University School of Medicine, Omaha, NE 68178, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Z. 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