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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 Ca2+-sensitive neuropeptide, somatostatin (SST), and an analog, octreotide, protect HCs from gentamicin-induced cell death in vitro. Aminoglycosides such as gentamicin trigger a calcium ion influx (Ca2+) that activates pro-apoptotic signaling cascades in HCs. SST binding to the G-protein-coupled receptors (SSTR1-SSTR5) that are directly linked to voltage-dependent Ca2+ channels inhibits Ca2+ channel activity and associated downstream events. Here, we report that the SST analog pasireotide, a high affinity ligand to SSTRs 1-3, and 5, with a longer half-life than octreotide, prevents gentamicin-induced 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-apoptotic effects. Mechanistically, pasireotide prevented a nuclear translocation of the Ca2+-sensitive transcription factor, nuclear factor of activated T cells (NFAT), which is ordinarily provoked by gentamicin in OC explants. Direct inhibition of NFAT with 11R-VIVIT also prevented the gentamicin-dependent nuclear translocation of NFAT and apoptosis. Both pasireotide and 11R-VIVIT partially reversed the effects of gentamicin on the expression of downstream survival targets (NMDA receptor and the regulatory subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase, PI3K). These data suggest that SST analogs antagonize aminoglycoside-induced cell death in an NFAT-dependent fashion. SST analogs and NFAT inhibitors may therefore offer new therapeutic possibilities for the treatment of hearing loss. [ABSTRACT FROM AUTHOR]