title: Pasireotide prevents nuclear factor of activated T cells nuclear translocation and acts as a protective agent in aminoglycoside-induced auditory hair cell loss.
abstract: 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.
authors: Department of Biomedicine and the Clinic for Otorhinolaryngology, University Hospital Basel, Basel, Switzerland.
authors: Daniel
authors: D
authors: Bodmer
authors: Department of Biomedicine and the Clinic for Otorhinolaryngology, University Hospital Basel, Basel, Switzerland.
authors: Adrijana
authors: A
authors: Perkovic
authors: Department of Biomedicine and the Clinic for Otorhinolaryngology, University Hospital Basel, Basel, Switzerland.
authors: Marijana
authors: M
authors: Sekulic-Jablanovic
authors: Strekin AG, Basel, Switzerland.
authors: Matthew B
authors: MB
authors: Wright
authors: Department of Biomedicine and the Clinic for Otorhinolaryngology, University Hospital Basel, Basel, Switzerland.
authors: Vesna
authors: V
authors: Petkovic
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology*; D000617:Aminoglycosides / Q000633:toxicity*; D000818:Animals; D005260:Female; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000378:metabolism*; D006728:Hormones / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009925:Organ of Corti / Q000187:drug effects / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000617:Aminoglycosides; D006728:Hormones; D050778:NFATC Transcription Factors; D018696:Neuroprotective Agents; D017481:Receptors, Somatostatin; C492049:Sstr2 protein, mouse; D013004:Somatostatin; C517782:pasireotide
keywords: NFAT; aminoglycoside toxicity; auditory hair cells; hearing loss; pasireotide; somatostatin receptors