{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T01:30:42Z","timestamp":1759541442625},"reference-count":43,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2016,11,29]],"date-time":"2016-11-29T00:00:00Z","timestamp":1480377600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label \/><jats:p>Hearing impairment is a global health problem with a high socioeconomic impact. Damage to auditory hair cells (HCs) in the inner ear as a result of aging, disease, trauma, or toxicity, underlies the majority of cases of sensorineural hearing loss. Previously we demonstrated that the Ca<jats:sup>2+<\/jats:sup>\u2010sensitive neuropeptide, somatostatin (SST), and an analog, octreotide, protect HCs from gentamicin\u2010induced cell death <jats:italic>in\u00a0vitro<\/jats:italic>. Aminoglycosides such as gentamicin trigger a calcium ion influx (Ca<jats:sup>2+<\/jats:sup>) that activates pro\u2010apoptotic signaling cascades in HCs. SST binding to the G\u2010protein\u2010coupled receptors (SSTR1\u2010SSTR5) that are directly linked to voltage\u2010dependent Ca<jats:sup>2+<\/jats:sup> channels inhibits Ca<jats:sup>2+<\/jats:sup> channel activity and associated downstream events. Here, we report that the SST analog pasireotide, a high affinity ligand to SSTRs 1\u20133, and 5, with a longer half\u2010life than octreotide, prevents gentamicin\u2010induced HC death in the mouse organ of Corti (OC). Explant experiments using OCs derived from SSTR1 and SSTR1and 2 knockout mice, revealed that SSTR2 mediates pasireotide's anti\u2010apoptotic effects. Mechanistically, pasireotide prevented a nuclear translocation of the Ca<jats:sup>2+<\/jats:sup>\u2010sensitive transcription factor, nuclear factor of activated T cells (NFAT), which is ordinarily provoked by gentamicin in OC explants. Direct inhibition of NFAT with 11R\u2010VIVIT also prevented the gentamicin\u2010dependent nuclear translocation of NFAT and apoptosis. Both pasireotide and 11R\u2010VIVIT partially reversed the effects of gentamicin on the expression of downstream survival targets (NMDA receptor and the regulatory subunit of phosphatidylinositol\u20104,5\u2010bisphosphate 3\u2010kinase, PI3K). These data suggest that SST analogs antagonize aminoglycoside\u2010induced cell death in an NFAT\u2010dependent fashion. SST analogs and NFAT inhibitors may therefore offer new therapeutic possibilities for the treatment of hearing loss.<\/jats:p><\/jats:sec><jats:sec><jats:label \/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13880-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13880","type":"journal-article","created":{"date-parts":[[2016,11,29]],"date-time":"2016-11-29T09:09:12Z","timestamp":1480410552000},"page":"1113-1123","source":"Crossref","is-referenced-by-count":6,"title":["Pasireotide prevents nuclear factor of activated T cells nuclear translocation and acts as a protective agent in aminoglycoside\u2010induced auditory hair cell loss"],"prefix":"10.1111","volume":"139","author":[{"given":"Daniel","family":"Bodmer","sequence":"first","affiliation":[{"name":"Department of Biomedicine and the Clinic for Otorhinolaryngology University Hospital Basel Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrijana","family":"Perkovic","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and the Clinic for Otorhinolaryngology University Hospital Basel Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marijana","family":"Sekulic\u2010Jablanovic","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and the Clinic for Otorhinolaryngology University Hospital Basel Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew B.","family":"Wright","sequence":"additional","affiliation":[{"name":"Strekin AG Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vesna","family":"Petkovic","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and the Clinic for Otorhinolaryngology University Hospital Basel Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,11,29]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1523\/JNEUROSCI.20-03-00929.2000","article-title":"Somatostatin modulates voltage\u2010gated K(+) and Ca(2\u00a0+\u00a0) currents in rod and cone photoreceptors of the salamander retina","volume":"20","author":"Akopian A.","year":"2000","journal-title":"J. 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