Targeting the somatostatin receptors as a therapeutic approach for the preservation and protection of the mammalian cochlea from excitotoxicity

Abstract

AbstractThe neuropeptide somatostatin (SST) is an important modulator of neurotransmission in the central nervous system (CNS) and binds to G-protein-coupled receptors (SSTR1-5) on target cells. Little is known about the expression and function of the somatostatinergic system in the mammalian cochlea. We analyzed the expression of SSTR1-SSTR5 in the immature mammalian cochlea. The peak in the expression of SSTR1 and SSTR2 at mRNA and protein level is around the onset of hearing to airborne sound, at postnatal day (P)14. This suggests their involvement in the maturation of the mammalian cochlea. We demonstrated that all five receptors are expressed in the inner hair cells (IHC) and outer hear cells (OHC) as well as in defined supporting cells of the organ of Corti (OC) in the adult mouse cochlea. A similar expression of the SSTRs in the IHC and OHC was found in cultivated P6 mouse OC explants as well as in neuroepithelial cell culture. In order to learn more about the regulation of SSTRs, we used mice with either a deletion of SSTR1, SSTR2 or SSTR1/SSTR2 double knock out (DKO). In DKO mice, SSTR5 was up-regulated and SSTR3 and SSTR4 were down regulated. These findings provide evidence of a compensatory regulation in the mammalian cochlea as a consequence of a receptor subtype deletion. In addition, we observed reduced levels of phospho-Akt and total-Akt in SSTR1 KO and DKO mice as compared to wild type (WT) mice. Akt is likely to be involved in hair cell survival. Most importantly, we found improved hair cell survival in somatostatin and octreotide treated OC explants that had been exposed to gentamicin compared to those explants exposed to gentamicin alone. These findings propose that the somatostatinergic system within the cochlea may have neuroprotective properties.