Role of somatostatin receptor-2 in gentamicin-induced auditory hair cell loss in the Mammalian inner ear

• Published in: PloS one 2014-09, Vol.9 (9), p.e108146
• Main Authors: Brand, Yves, Radojevic, Vesna, Sung, Michael, Wei, Eric, Setz, Cristian, Glutz, Andrea, Leitmeyer, Katharina, Bodmer, Daniel
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Aminoglycosides; Animals; Apoptosis; Auditory defects; Auditory system; Biology and life sciences; Cell culture; Cell cycle; Cell death; Cell Death - drug effects; Cell growth; Ear; Explants; Gene Expression Regulation; Gentamicin; Gentamicins; Hair; Hair cells; Hair Cells, Auditory - drug effects; Hair Cells, Auditory - metabolism; Hair Cells, Auditory - pathology; Hearing loss; Hearing Loss - chemically induced; Hearing Loss - genetics; Hearing Loss - physiopathology; Hearing Loss - prevention & control; Inner ear; Ischemia; Kinases; Mammals; Mice; Mice, Knockout; Mortality; Neurites - drug effects; Neurites - metabolism; Neurites - ultrastructure; Octreotide; Octreotide - pharmacology; Organ Culture Techniques; Organ of Corti; Otolaryngology; Phosphorylation; Phosphorylation - drug effects; Protective Agents - pharmacology; Protein kinase; Proteins; Proto-Oncogene Proteins c-akt - agonists; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Receptors; Receptors, Somatostatin - deficiency; Receptors, Somatostatin - genetics; Retina; Rodents; Signal Transduction; Signaling; Somatostatin; Somatostatin receptors; Spiral ganglion; Spiral Ganglion - drug effects; Spiral Ganglion - metabolism; Spiral Ganglion - ultrastructure; Studies; Surgery; Toxicity
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0108146

Hair cells and spiral ganglion neurons of the mammalian auditory system do not regenerate, and their loss leads to irreversible hearing loss. Aminoglycosides induce auditory hair cell death in vitro, and evidence suggests that phosphatidylinositol-3-kinase/Akt signaling opposes gentamicin toxicity via its downstream target, the protein kinase Akt. We previously demonstrated that somatostatin-a peptide with hormone/neurotransmitter properties-can protect hair cells from gentamicin-induced hair cell death in vitro, and that somatostatin receptors are expressed in the mammalian inner ear. However, it remains unknown how this protective effect is mediated. In the present study, we show a highly significant protective effect of octreotide (a drug that mimics and is more potent than somatostatin) on gentamicin-induced hair cell death, and increased Akt phosphorylation in octreotide-treated organ of Corti explants in vitro. Moreover, we demonstrate that somatostatin receptor-1 knockout mice overexpress somatostatin receptor-2 in the organ of Corti, and are less susceptible to gentamicin-induced hair cell loss than wild-type or somatostatin-1/somatostatin-2 double-knockout mice. Finally, we show that octreotide affects auditory hair cells, enhances spiral ganglion neurite number, and decreases spiral ganglion neurite length.