Pasireotide prevents nuclear factor of activated T cells nuclear translocation and acts as a protective agent in aminoglycoside‐induced auditory hair cell loss. Issue 6 (29th November 2016)

• Record Type: Journal Article
• Authors: Bodmer, Daniel; Perkovic, Adrijana; Sekulic‐Jablanovic, Marijana; Wright, Matthew B.; Petkovic, Vesna
• Is Part Of: Journal of neurochemistry. Volume 139:Issue 6(2016)
• Page Start: 1113
• Page End: 1123
• Publication Date: 2016-11-29
• Subjects: aminoglycoside toxicity -- auditory hair cells -- hearing loss -- NFAT -- pasireotide -- somatostatin receptors; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.13880
• Languages: English
• ISSNs: 0022-3042

Abstract

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 Ca 2+ ‐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 (Ca 2+ ) 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 Ca 2+ channels inhibits Ca 2+ 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 Ca 2+ ‐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 : Aminoglycosides such as gentamicin trigger a calcium ion influx (Ca 2+ ) that activates pro‐apoptotic signaling cascades in auditory hair cells (HCs). Pasireotide inhibits Ca 2+ channel activity, preventing the accumulation of cellular Ca 2+ provoked by gentamicin, thereby preventing the downstream events that culminate in nuclear factor of activated T cells (NFAT) activation. The cell‐permeable peptide 11R‐VIVIT interrupts the same pathway by binding to Calcineurin (CaN), selectively blocking its ability to activate NFAT. Our discovery of the protective effects of pasireotide and 11R‐VIVIT, together with the characterization of their mechanism of action, suggests how we can rapidly reformulate a well‐known drug for entry into clinical trials as a potential new therapy for hearing loss.